|
inhibitory concentration required to inhibit neuraminidase enzyme from different strains of influenza A virus
|
Influenza A virus
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design.
Year : 2000
Volume : 43
Issue : 19
First Page : 3482
Last Page : 3486
Authors : Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA.
|
inhibitory concentration required to inhibit neuraminidase enzyme from different strains of influenza B virus.
|
Influenza B virus
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design.
Year : 2000
Volume : 43
Issue : 19
First Page : 3482
Last Page : 3486
Authors : Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA.
|
Inhibitory activity against influenza A neuraminidase
|
Influenza A virus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity.
Year : 2001
Volume : 44
Issue : 25
First Page : 4379
Last Page : 4392
Authors : Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Babu YS, Bantia S, Elliott AJ, Montgomery JA.
Abstract : The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor-enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC(50) values vs neuraminidase from influenza A and B of <1 and <10 nM, respectively. These IC(50) values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.
|
Inhibitory activity against influenza B neuraminidase
|
Influenza B virus
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity.
Year : 2001
Volume : 44
Issue : 25
First Page : 4379
Last Page : 4392
Authors : Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Babu YS, Bantia S, Elliott AJ, Montgomery JA.
Abstract : The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor-enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC(50) values vs neuraminidase from influenza A and B of <1 and <10 nM, respectively. These IC(50) values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.
|
Antiviral activity against influenza H1N1 virus
|
Influenza A virus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.
Year : 2009
Volume : 17
Issue : 2
First Page : 569
Last Page : 575
Authors : Prado-Prado FJ, Martinez de la Vega O, Uriarte E, Ubeira FM, Chou KC, González-Díaz H.
Abstract : One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the model in practice, we develop a virtual screening recognizing the model as active 92.7%, 102 of 110 antivirus compounds. These compounds were never use in training or predicting series. Next, we obtained and compared the topology of the CNs and their respective GCs based on Euclidean, Manhattan, Chebychey, Pearson and other similarity measures. The GC of the Manhattan network showed the more interesting features for drug-drug similarity search. We also give the procedure for the construction of Back-Projection Maps for the contribution of each drug sub-structure to the antiviral activity against different species.
|
Inhibition of Influenza B virus (B/Perth/211/2001) recombinant wild type neuraminidase expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
1.2
nM
|
|
Inhibition of Influenza B virus (B/Perth/211/2001) recombinant wild type neuraminidase expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
27.8
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus (B/Perth/211/2001) recombinant neuraminidase E197 mutant expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
8.3
nM
|
|
Inhibition of Influenza B virus (B/Perth/211/2001) recombinant neuraminidase E197 mutant expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
75.2
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus (B/Perth/211/2001) wild type recombinant neuraminidase expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
0.6
nM
|
|
Inhibition of Influenza B virus (B/Perth/211/2001) wild type recombinant neuraminidase expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
2.8
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus (B/Perth/211/2001) recombinant neuraminidase E197 mutant expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
8.2
nM
|
|
Inhibition of Influenza B virus (B/Perth/211/2001) recombinant neuraminidase E197 mutant expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus (B/Perth/211/2001)
|
41.5
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus B/Gifu/11/2005 wild type neuraminidase expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus
|
0.7
nM
|
|
Inhibition of Influenza B virus B/Gifu/11/2005 wild type neuraminidase expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus B/Yamagata/186/05 neuraminidase N197 mutant expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus
|
3.2
nM
|
|
Inhibition of Influenza B virus B/Yamagata/186/05 neuraminidase N197 mutant expressed in Sf21 insect cells after 60 mins by MUNANA based assay
|
Influenza B virus
|
28.1
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus B/Gifu/11/2005 wild type neuraminidase expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus
|
0.3
nM
|
|
Inhibition of Influenza B virus B/Gifu/11/2005 wild type neuraminidase expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Inhibition of Influenza B virus B/Yamagata/186/05 neuraminidase N197 mutant expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus
|
2.3
nM
|
|
Inhibition of Influenza B virus B/Yamagata/186/05 neuraminidase N197 mutant expressed in Sf21 insect cells preincubated for 30 mins measured after 60 mins by MUNANA based assay
|
Influenza B virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.
Year : 2010
Volume : 53
Issue : 17
First Page : 6421
Last Page : 6431
Authors : Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL.
Abstract : We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir.
|
Antiviral activity against Influenza A virus (A/Texas/12/2007 (H3N2)) with neuraminidase E119(V/I) mutant isolated from immunocompromized patient measured after X/CD3 additional passages in MDCK cells by NA inhibition assay
|
Influenza A virus (A/Texas/12/2007(H3N2))
|
0.51
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Texas/12/2007 (H3N2)) clone 1 with neuraminidase E119V mutant isolated from immunocompromized patient measured after X/CD4 additional passages in MDCK cells by NA inhibition assay
|
Influenza A virus (A/Texas/12/2007(H3N2))
|
0.43
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Texas/12/2007 (H3N2)) clone 2 with neuraminidase E119I mutant isolated from immunocompromized patient measured after X/CD4 additional passages in MDCK cells by NA inhibition assay
|
Influenza A virus (A/Texas/12/2007(H3N2))
|
0.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Washington/01/2007 (H3N2)) measured in MDCK cells by NA inhibition assay
|
Influenza A virus (A/Washington/01/2007(H3N2))
|
0.28
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against sInfluenza A virus (A/Texas/12/2007 (H3N2)) with neuraminidase E119(V/I) mutant isolated from immunocompromized patient measured after X/CD3 additional passages in MDCK cells by fluorescent NA inhibition assay
|
Influenza A virus (A/Texas/12/2007(H3N2))
|
33.56
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Texas/12/2007 (H3N2)) clone 1 with neuraminidase E119V mutant isolated from immunocompromized patient measured after X/CD4 additional passages in MDCK cells by fluorescent NA inhibition assay
|
Influenza A virus (A/Texas/12/2007(H3N2))
|
1.47
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Texas/12/2007 (H3N2)) clone 2 with neuraminidase E119I mutant isolated from immunocompromized patient measured after X/CD4 additional passages in MDCK cells by fluorescent NA inhibition assay
|
Influenza A virus (A/Texas/12/2007(H3N2))
|
214.07
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Washington/01/2007 (H3N2)) measured in MDCK cells by fluorescent NA inhibition assay
|
Influenza A virus (A/Washington/01/2007(H3N2))
|
0.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.
Year : 2010
Volume : 54
Issue : 5
First Page : 1834
Last Page : 1841
Authors : Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV.
Abstract : The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring neuraminidase I222V mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring neuraminidase I222M and H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
891.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring neuraminidase H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
142.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring neuraminidase I222M mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring neuraminidase I222V and H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
562.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring neuraminidase E119G mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
43.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring neuraminidase H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring wild type neuraminidase
|
Influenza A virus (A/environment/Viet Nam/1203/2004(H5N1))
|
27.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring neuraminidase D198G mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring wild type neuraminidase
|
Influenza A virus (A/environment/Viet Nam/1203/2004(H5N1))
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring neuraminidase E119G mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring wild type neuraminidase
|
Influenza A virus (A/environment/Viet Nam/1203/2004(H5N1))
|
3.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring neuraminidase I222M mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase
|
Influenza A virus (A/New Caledonia/20/1999(H1N1))
|
0.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring neuraminidase H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase
|
Influenza A virus (A/New Caledonia/20/1999(H1N1))
|
82.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring neuraminidase I222M and H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase
|
Influenza A virus (A/New Caledonia/20/1999(H1N1))
|
95.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring neuraminidase I222V mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase
|
Influenza A virus (A/New Caledonia/20/1999(H1N1))
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring neuraminidase I222V and H274Y mutant infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase
|
Influenza A virus (A/New Caledonia/20/1999(H1N1))
|
213.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Chicken/Laos/26/2006(H5N1)) harboring wild type neuraminidase infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose
|
Influenza A virus (A/Chicken/Laos/Xaythiani 26/2006(H5N1))
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring wild type neuraminidase infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus (A/Vietnam/1203/2004 (H5N1)) harboring wild type neuraminidase
|
Influenza A virus (A/environment/Viet Nam/1203/2004(H5N1))
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase infected in MDCK cells assessed as inhibition of viral-induced cytopathogenicity after 4 days post dose to IC50 for Influenza A virus A/New Caledonia/20/99 (H1N1)) harboring wild type neuraminidase
|
Influenza A virus (A/New Caledonia/20/1999(H1N1))
|
0.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.
Year : 2009
Volume : 53
Issue : 10
First Page : 4433
Last Page : 4440
Authors : Hurt AC, Holien JK, Barr IG.
Abstract : To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
|
Antiviral activity against influenza A (A/Washington/10/2008 (H1N1)) virus after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
0.11
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/North Carolina/02/2009 (H1N1)) virus after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
0.08
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/New York/18/2009 (H1N1)) virus after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
0.12
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/29/2009 (H1N1)) virus after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
0.14
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Singapore/91/2009 (H1N1)) virus after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
0.11
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/North Carolina/01/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
13.75
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Montana/02/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
14.96
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Osaka/180/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
13.06
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/29/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
12.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Hong Kong/2369/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
9.24
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Singapore/57/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by NA-star substrate based chemiluminescent assay
|
Influenza A virus
|
11.79
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/10/2008 (H1N1)) virus after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
0.18
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/North Carolina/02/2009 (H1N1)) virus after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
0.19
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/New York/18/2009 (H1N1)) virus after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
0.32
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/29/2009 (H1N1)) virus after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
0.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Singapore/91/2009 (H1N1)) virus after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
0.14
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/North Carolina/01/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
149.59
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Montana/02/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
197.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Osaka/180/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
97.56
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/29/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
150.24
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Hong Kong/2369/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
128.15
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Singapore/57/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 30 mins by MUNANA substrate based fluorometric assay
|
Influenza A virus
|
121.76
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/10/2008 (H1N1)) virus after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
0.75
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/North Carolina/02/2009 (H1N1)) virus after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
0.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/New York/18/2009 (H1N1)) virus after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
0.41
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/29/2009 (H1N1)) virus after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
0.49
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Singapore/91/2009 (H1N1)) virus after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
0.55
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/North Carolina/01/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
105.02
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Montana/02/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
83.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Osaka/180/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
194.96
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Washington/29/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
162.58
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Hong Kong/2369/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
161.79
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A (A/Singapore/57/2009 (H1N1)) virus harboring neuraminidase H275Y mutant after 16 to 18 hrs by fetuin substrate based colorimetric assay
|
Influenza A virus
|
84.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.
Year : 2010
Volume : 54
Issue : 9
First Page : 3671
Last Page : 3677
Authors : Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV.
Abstract : The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
|
Antiviral activity against influenza A virus H1N1 infected in MDCK cells assessed as inhibition of neuraminidase activity by fluorimetric assay
|
Influenza A virus
|
9.43
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against influenza A virus H3N2 infected in MDCK cells assessed as inhibition of neuraminidase activity by fluorimetric assay
|
Influenza A virus
|
3.51
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against influenza A virus infected in MDCK cells assessed as inhibition of neuraminidase activity by fluorimetric assay
|
Influenza A virus
|
1.72
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against influenza B virus infected in MDCK cells assessed as inhibition of neuraminidase activity by fluorimetric assay
|
Influenza B virus
|
3.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against Influenza virus infected in human patient assessed as decrease in virus-positive patients at 300 mg, iv on day 3
|
unidentified influenza virus
|
36.8
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against Influenza virus infected in human patient assessed as decrease in virus-positive patients at 600 mg, iv on day 3
|
unidentified influenza virus
|
25.8
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against Influenza virus infected in human patient assessed as decrease in virus-positive patients at 300 mg, iv on day 9
|
unidentified influenza virus
|
0.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against Influenza virus infected in human patient assessed as decrease in virus-positive patients at 600 mg, iv on day 9
|
unidentified influenza virus
|
1.1
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Year : 2010
Volume : 54
Issue : 11
First Page : 4568
Last Page : 4574
Authors : Kohno S, Kida H, Mizuguchi M, Shimada J, S-021812 Clinical Study Group.
Abstract : Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
|
Antiviral activity against NP40-inactivated Influenza A virus (A/Brisbane/59/2007(H1N1)) preincubated with virus for 10 mins by viral hemagglutinination titter assay
|
Influenza A virus (A/Brisbane/59/2007(H1N1))
|
0.86
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase.
Year : 2011
Volume : 21
Issue : 23
First Page : 7137
Last Page : 7141
Authors : Bromba CM, Mason JW, Brant MG, Chan T, Lunke MD, Petric M, Boulanger MJ, Wulff JE.
Abstract : The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.
|
Antiviral activity against NP40-inactivated Influenza A virus (A/Brisbane/59/2007(H1N1)) preincubated with virus for 2 hrs by viral hemagglutinination titter assay
|
Influenza A virus (A/Brisbane/59/2007(H1N1))
|
0.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase.
Year : 2011
Volume : 21
Issue : 23
First Page : 7137
Last Page : 7141
Authors : Bromba CM, Mason JW, Brant MG, Chan T, Lunke MD, Petric M, Boulanger MJ, Wulff JE.
Abstract : The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.
|
Inhibition of Influenza A virus (A/Brevig Mission/1/1918(H1N1)) recombinant soluble neuraminidase using 2'-4(methylumbelliferyl)-alpha-D-N-acetylneuraminic acid substrate by fluorimetric assay
|
Influenza A virus (A/Brevig Mission/1/1918(H1N1))
|
3.4
nM
|
|
Inhibition of Influenza A virus (A/Brevig Mission/1/1918(H1N1)) recombinant soluble neuraminidase using 2'-4(methylumbelliferyl)-alpha-D-N-acetylneuraminic acid substrate by fluorimetric assay
|
Influenza A virus (A/Brevig Mission/1/1918(H1N1))
|
0.83
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase.
Year : 2011
Volume : 21
Issue : 23
First Page : 7137
Last Page : 7141
Authors : Bromba CM, Mason JW, Brant MG, Chan T, Lunke MD, Petric M, Boulanger MJ, Wulff JE.
Abstract : The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.
|
Inhibition of influenza virus neuraminidase
|
unidentified adenovirus
|
0.1
nM
|
|
Journal : MedChemComm
Title : Conformational analysis of peramivir reveals critical differences between free and enzyme-bound states
Year : 2014
Volume : 5
Issue : 10
First Page : 1483
Last Page : 1488
Authors : Richards MR, Brant MG, Boulanger MJ, Cairo CW, Wulff JE
|
Inhibition of oseltamivir-resistant Influenza A virus A/WSN/1933(H1N1) recombinant wild type neuraminidase transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/WSN/1933(H1N1))
|
0.07
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Antiviral activity against oseltamivir-resistant Influenza A virus A/WSN/1933(H1N1) infected in MDCK cells assessed as protection against virus-induced cytopathic effect after 48 hrs by CellTiter 96 AQueous Non-Radioactive cell proliferation assay
|
Influenza A virus (A/WSN/1933(H1N1))
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of Influenza A virus A/WSN/1933(H1N1) recombinant neuraminidase H275Y mutant transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/WSN/1933(H1N1))
|
3.6
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of Influenza A virus A/Brisbane/10/2007(H3N2) recombinant wild type neuraminidase transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/Brisbane/10/2007(H3N2))
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of Influenza A virus A/Brisbane/10/2007(H3N2) recombinant neuraminidase E119A mutant transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/Brisbane/10/2007(H3N2))
|
225.0
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of Influenza A virus A/Brisbane/10/2007(H3N2) recombinant neuraminidase R292K mutant transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/Brisbane/10/2007(H3N2))
|
146.0
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of oseltamivir-resistant Influenza A virus A/Vietnam/1194/2004(H5N1) recombinant wild type neuraminidase transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/Vietnam/1194/2004(H5N1))
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of oseltamivir-resistant Influenza A virus A/Vietnam/1194/2004(H5N1) recombinant neuraminidase H275Y mutant transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/Vietnam/1194/2004(H5N1))
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of Influenza A virus A/Shanghai/01/2014(H7N9) recombinant wild type neuraminidase transfected in HEK293 cells using MUNANA as substrate assessed as release of 4-methylumbelliferone preincubated for 10 mins followed by substrate addition measured after 15 mins by fluorometric assay
|
Influenza A virus (A/Shanghai/01/2014(H7N9))
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.
Year : 2016
Volume : 59
Issue : 11
First Page : 5297
Last Page : 5310
Authors : Wang PC, Fang JM, Tsai KC, Wang SY, Huang WI, Tseng YC, Cheng YS, Cheng TJ, Wong CH.
Abstract : Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
|
Inhibition of Influenza A virus (A/WSN/1933(H1N1)) neuraminidase pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/WSN/1933(H1N1))
|
0.48
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Antiviral activity against Influenza A virus (A/WSN/1933(H1N1)) infected in MDCK cells assessed as inhibition of virus-induced cytopathic effect after 48 hrs by CellTiter96 Aqueous non-radioactive cell proliferation assay
|
Influenza A virus (A/WSN/1933(H1N1))
|
6.68
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/WSN/1933(H1N1)) neuraminidase H275Y mutant pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/WSN/1933(H1N1))
|
23.1
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Antiviral activity against Influenza A virus (A/WSN/1933(H1N1)) harboring neuraminidase H275Y mutant infected in MDCK cells assessed as inhibition of virus-induced cytopathic effect after 48 hrs by CellTiter96 Aqueous non-radioactive cell proliferation assay
|
Influenza A virus (A/WSN/1933(H1N1))
|
643.0
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/WSN/1933(H1N1)) recombinant neuraminidase expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/WSN/1933(H1N1))
|
0.4
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/WSN/1933(H1N1)) recombinant neuraminidase H275Y mutant expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/WSN/1933(H1N1))
|
3.6
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Vietnam/1194/2004 (H5N1)) recombinant neuraminidase expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Vietnam/1194/2004(H5N1))
|
0.3
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Vietnam/1194/2004 (H5N1)) recombinant neuraminidase H275Y mutant expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Vietnam/1194/2004(H5N1))
|
18.4
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Brisbane/10/2007(H3N2)) recombinant neuraminidase expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Brisbane/10/2007(H3N2))
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Vietnam/1194/2004 (H5N1)) recombinant neuraminidase E119A mutant expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Brisbane/10/2007(H3N2))
|
451.0
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Vietnam/1194/2004 (H5N1)) recombinant neuraminidase R292K mutant expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Brisbane/59/2007(H1N1))
|
146.0
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Shanghai/01/2014(H7N9)) recombinant neuraminidase expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Shanghai/01/2014(H7N9))
|
16.7
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Inhibition of Influenza A virus (A/Shanghai/01/2014(H7N9)) recombinant neuraminidase R292K mutant expressed in HEK293 cells pre-incubated for 10 mins before 4-MUNANA substrate addition by fluorometry
|
Influenza A virus (A/Shanghai/01/2014(H7N9))
|
92.5
nM
|
|
Journal : Eur J Med Chem
Title : Peramivir conjugates as orally available agents against influenza H275Y mutant.
Year : 2018
Volume : 145
First Page : 224
Last Page : 234
Authors : Wang PC, Chiu DC, Jan JT, Huang WI, Tseng YC, Li TT, Cheng TJ, Tsai KC, Fang JM.
Abstract : Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
9.66
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.19
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.502
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.05
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.05
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
