|
Dissociation constant with dimeric 16S rRNA RNA construct B
|
None
|
350.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel synthesis and RNA-binding properties of aminoglycoside dimers conjugated via a naphthalene diimide-based intercalator.
Year : 2001
Volume : 11
Issue : 22
First Page : 2987
Last Page : 2991
Authors : Tok JB, Fenker J.
Abstract : The synthesis and RNA-binding properties of naphthalene-based diimide conjugated bis-aminoglycoside antibiotics are reported. Compared to the monomeric aminoglycoside, the conjugated ligands were observed to attain up to 35-fold enhancement in binding affinity towards a novel RNA construct that contained two 16S rRNA A-sites.
|
Dissociation constant towards 16S rRNA construct A
|
None
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhanced binding of aminoglycoside dimers to a "dimerized" A-site 16S rRNA construct.
Year : 2000
Volume : 10
Issue : 14
First Page : 1593
Last Page : 1595
Authors : Tok JB, Huffman GR.
Abstract : In this work, we investigated the binding of a series of dimeric aminoglycoside molecules to (i) a 27 nt A-site 16S rRNA construct, and (ii) an artificially grafted 46 nt 'dimerized' A-site 16S rRNA construct. It was observed that the dissociation constants of dimeric aminoglycosides to the dimerized A-site 16S rRNA construct can achieve up to approximately 19-fold enhancement compared to the monomeric aminoglycoside molecules.
|
Dissociation constant towards 16S rRNA construct B
|
None
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhanced binding of aminoglycoside dimers to a "dimerized" A-site 16S rRNA construct.
Year : 2000
Volume : 10
Issue : 14
First Page : 1593
Last Page : 1595
Authors : Tok JB, Huffman GR.
Abstract : In this work, we investigated the binding of a series of dimeric aminoglycoside molecules to (i) a 27 nt A-site 16S rRNA construct, and (ii) an artificially grafted 46 nt 'dimerized' A-site 16S rRNA construct. It was observed that the dissociation constants of dimeric aminoglycosides to the dimerized A-site 16S rRNA construct can achieve up to approximately 19-fold enhancement compared to the monomeric aminoglycoside molecules.
|
Binding affinity of aminoglycoside to 16S ribosomal RNA A-site in Escherichia coli
|
Escherichia coli
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Which aminoglycoside ring is most important for binding? A hydropathic analysis of gentamicin, paromomycin, and analogues.
Year : 2001
Volume : 11
Issue : 2
First Page : 119
Last Page : 122
Authors : Cashman DJ, Rife JP, Kellogg GE.
Abstract : The NMR structures of gentamicin and paromomycin in complex with the A-site of Escherichia coli 16S ribosomal RNA were modified with molecular modeling to 12 analogues. The intermolecular interactions between these molecules and RNA were examined using the HINT (Hydropathic INTeractions) computational model to obtain interaction scores that have been shown previously to be related to free energy. The calculations correlated well with experimental binding data, and the interaction scores were used to analyze the specific structural features of each aminoglycoside that contribute to the overall binding with the 16S rRNA. Our calculations indicate that, while ring I binds to the main binding pocket of the rRNA A-site, ring IV of paromomycin-based aminoglycosides contributes significantly to the overall binding.
|
Tested for the ability to bind the HIV-1 RRE-RNA construct by fluorescence anisotropy
|
None
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding of dimeric aminoglycosides to the HIV-1 rev responsive element (RRE) RNA construct.
Year : 2001
Volume : 11
Issue : 9
First Page : 1127
Last Page : 1131
Authors : Tok JB, Dunn LJ, Des Jean RC.
Abstract : Through a series of elegant fluorescence measurements, particularly through stopped-flow kinetic measurements, it was recently demonstrated that aminoglycoside antibiotics are able to bind to the HIV-1 Rev responsive element (RRE) RNA construct in more than a 1:1 stoichiometry (Lacourciere, K. A.; Stivers, J. T.; Marino, J. P. Biocheminstry 2000, 39, 5630). Here, we present the binding study results of dimeric neomycin ligands through fluorescence anisotropy studies, to the HIV-1 RRE RNA construct. The dimeric neomycin molecules are observed to be able to bind the HIV-1 RRE RNA construct approximately 17-fold higher when compared to the monomeric neomycin, lending evidence that there are indeed two or more neomycin binding sites within the HIV-1 RRE construct.
|
Inhibitory activity against the displacement of Picogreen from fMet-tRNA(fMet) by the aminoglycoside
|
Staphylococcus aureus
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Inhibitory activity of the aminoglycoside on Staphylococcus aureus IF-2 binding to fMet-tRNA(fMet)
|
Staphylococcus aureus
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Maximal inhibition against the displacement of Picogreen from fMet-tRNA(fMet) by the aminoglycoside
|
Staphylococcus aureus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Maximal inhibition of the aminoglycoside on Staphylococcus aureus IF-2 binding to fMet-tRNA(fMet)
|
Staphylococcus aureus
|
76.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides.
Year : 2003
Volume : 13
Issue : 6
First Page : 993
Last Page : 996
Authors : Evans JM, Turner BA, Bowen S, Ho AM, Sarver RW, Benson E, Parker CN.
Abstract : Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction. Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity. However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)). This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.
|
Dissociation constant for binding to mitochondrial 12S rRNA construct M2 was determined
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Decoding region bubble size and aminoglycoside antibiotic binding.
Year : 2002
Volume : 12
Issue : 16
First Page : 2241
Last Page : 2244
Authors : Ryu DH, Rando RR.
Abstract : Aminoglycoside antibiotics promiscuously bind to structurally diverse RNA molecules containing internal bubbles and bulges with affinities in the microM range. An interesting exception is found in the human 12S mitochondrial decoding region where aminoglycoside binding, unlike in the case of its bacterial and human cytoplasmic counterparts, is absent. Mutations that reduce the size of the bubble in the 12S decoding region immediately restore aminoglycoside binding, giving the system chemical switch like behavior.
|
Dissociation constant for binding to mitochondrial 12S rRNA construct M3 was determined
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Decoding region bubble size and aminoglycoside antibiotic binding.
Year : 2002
Volume : 12
Issue : 16
First Page : 2241
Last Page : 2244
Authors : Ryu DH, Rando RR.
Abstract : Aminoglycoside antibiotics promiscuously bind to structurally diverse RNA molecules containing internal bubbles and bulges with affinities in the microM range. An interesting exception is found in the human 12S mitochondrial decoding region where aminoglycoside binding, unlike in the case of its bacterial and human cytoplasmic counterparts, is absent. Mutations that reduce the size of the bubble in the 12S decoding region immediately restore aminoglycoside binding, giving the system chemical switch like behavior.
|
Dissociation constant for binding to mitochondrial 12S rRNA construct M4 was determined
|
Homo sapiens
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Decoding region bubble size and aminoglycoside antibiotic binding.
Year : 2002
Volume : 12
Issue : 16
First Page : 2241
Last Page : 2244
Authors : Ryu DH, Rando RR.
Abstract : Aminoglycoside antibiotics promiscuously bind to structurally diverse RNA molecules containing internal bubbles and bulges with affinities in the microM range. An interesting exception is found in the human 12S mitochondrial decoding region where aminoglycoside binding, unlike in the case of its bacterial and human cytoplasmic counterparts, is absent. Mutations that reduce the size of the bubble in the 12S decoding region immediately restore aminoglycoside binding, giving the system chemical switch like behavior.
|
Tested for binding affinity against RNA construct A
|
None
|
410.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding of aminoglycoside antibiotics with modified A-site 16S rRNA construct containing non-nucleotide linkers.
Year : 2002
Volume : 12
Issue : 3
First Page : 365
Last Page : 370
Authors : Tok JB, Wong W, Baboolal N.
Abstract : The design and synthesis of synthetically modified cyclic A-site 16S rRNA construct is reported. The binding characteristics of several members of the aminoglycoside antibiotics with this novel class of synthetically modified A-site 16S rRNA constructs were subsequently investigated.
|
Tested for binding affinity against RNA construct B
|
None
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding of aminoglycoside antibiotics with modified A-site 16S rRNA construct containing non-nucleotide linkers.
Year : 2002
Volume : 12
Issue : 3
First Page : 365
Last Page : 370
Authors : Tok JB, Wong W, Baboolal N.
Abstract : The design and synthesis of synthetically modified cyclic A-site 16S rRNA construct is reported. The binding characteristics of several members of the aminoglycoside antibiotics with this novel class of synthetically modified A-site 16S rRNA constructs were subsequently investigated.
|
Tested for binding affinity against RNA construct D
|
None
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding of aminoglycoside antibiotics with modified A-site 16S rRNA construct containing non-nucleotide linkers.
Year : 2002
Volume : 12
Issue : 3
First Page : 365
Last Page : 370
Authors : Tok JB, Wong W, Baboolal N.
Abstract : The design and synthesis of synthetically modified cyclic A-site 16S rRNA construct is reported. The binding characteristics of several members of the aminoglycoside antibiotics with this novel class of synthetically modified A-site 16S rRNA constructs were subsequently investigated.
|
Tested for binding affinity against RNA construct E
|
None
|
91.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Binding of aminoglycoside antibiotics with modified A-site 16S rRNA construct containing non-nucleotide linkers.
Year : 2002
Volume : 12
Issue : 3
First Page : 365
Last Page : 370
Authors : Tok JB, Wong W, Baboolal N.
Abstract : The design and synthesis of synthetically modified cyclic A-site 16S rRNA construct is reported. The binding characteristics of several members of the aminoglycoside antibiotics with this novel class of synthetically modified A-site 16S rRNA constructs were subsequently investigated.
|
Concentration required for the inhibition of HIV- 1 Tat-derived peptide binding to TAR RNA.
|
None
|
920.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of an HIV-1 Tat-derived peptide binding to TAR RNA by aminoglycoside antibiotics
Year : 1995
Volume : 5
Issue : 22
First Page : 2755
Last Page : 2760
Authors : Mei H, Galan AA, Halim NS, Mack DP, Moreland DW, Sanders KB, Hoa N. Truong, Czarnik AW
|
Dissociation constant of the compound
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Validation of automated docking programs for docking and database screening against RNA drug targets.
Year : 2004
Volume : 47
Issue : 17
First Page : 4188
Last Page : 4201
Authors : Detering C, Varani G.
Abstract : The increasing awareness of the essential role of RNA in controlling viral replication and in bacterial protein synthesis emphasizes the potential of ribonucleoproteins as targets for developing new antibacterial and antiviral drugs. RNA forms well defined three-dimensional structures with clefts and binding pockets reminiscent of the active sites of proteins. Furthermore, it precedes proteins in the translation pathway; inhibiting the function of a single RNA molecule would result in inhibition of multiple proteins. Thus, small molecules that bind RNA specifically would combine the advantages of antisense and RNAi strategies with the much more favorable medicinal chemistry of small-molecule therapeutics. The discovery of small-molecule inhibitors of RNA with attractive pharmacological potential would be facilitated if we had available effective computational tools of structure-based drug design. Here, we systematically test automated docking tools developed for proteins using existing three-dimensional structures of RNA-small molecule complexes. The results show that the native structures can generally be reproduced to within 2.5 angstroms more than 50-60% of the time. For more than half of the test complexes, the native ligand ranked among the top 10% compounds in a database-scoring test. Through this work, we provide parameters for the validated application of automated docking tools to the discovery of new inhibitors of RNA function.
|
Inhibition of anthrax lethal factor metalloprotease
|
Bacillus anthracis
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selectively guanidinylated derivatives of neamine. Syntheses and inhibition of anthrax lethal factor protease.
Year : 2006
Volume : 16
Issue : 19
First Page : 5183
Last Page : 5189
Authors : Jiao GS, Simo O, Nagata M, O'Malley S, Hemscheidt T, Cregar L, Millis SZ, Goldman ME, Tang C.
Abstract : A series of mono-, di-, and tri-guanidinylated derivatives of neamine were prepared via selective guanidinylation of neamine. These molecules represent a novel scaffold as inhibitors of anthrax lethal factor zinc metalloprotease. Methods for the synthesis of these compounds are described, and structure-activity relationships among the series are analyzed. In addition, initial findings regarding the mechanism of LF inhibition for these molecules are presented.
|
Binding affinity to Rev response element RNA
|
None
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A strategy for the design of selective RNA binding agents. Preparation and RRE RNA binding affinities of a neomycin-peptide nucleic acid heteroconjugate library.
Year : 2006
Volume : 16
Issue : 18
First Page : 4757
Last Page : 4759
Authors : Hyun S, Lee KH, Yu J.
Abstract : We have successfully developed a new strategy for RNA ligand design, which applies the antisense concept to enhance and make more specific loop region interactions while at the same time preserving stem region anchoring. The heteroconjugates, prepared in this effort, have proven to be the most specific small molecule ligands against RRE RNA that have been uncovered to date.
|
Binding affinity to tRNA
|
None
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A strategy for the design of selective RNA binding agents. Preparation and RRE RNA binding affinities of a neomycin-peptide nucleic acid heteroconjugate library.
Year : 2006
Volume : 16
Issue : 18
First Page : 4757
Last Page : 4759
Authors : Hyun S, Lee KH, Yu J.
Abstract : We have successfully developed a new strategy for RNA ligand design, which applies the antisense concept to enhance and make more specific loop region interactions while at the same time preserving stem region anchoring. The heteroconjugates, prepared in this effort, have proven to be the most specific small molecule ligands against RRE RNA that have been uncovered to date.
|
Binding affinity to Escherichia coli K12 stem-loop region L2-10 RNA aptamers using luminescence spectrometer by anisotropy technique
|
Escherichia coli
|
308.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Elucidation of the RNA target of linezolid by using a linezolid-neomycin B heteroconjugate and genomic SELEX.
Year : 2007
Volume : 15
Issue : 24
First Page : 7688
Last Page : 7695
Authors : Kim HJ, Kwon M, Yu J.
Abstract : A covalently modified heteroconjugate between linezolid and neomycin B leads to an enhanced and more specific binding affinity to hairpin RNA targets in comparison to neomycin B itself. This heteroconjugate was used as a lure to select linezolid-specific hairpin RNA from an Escherichia coli genome RNA. The selected RNA obtained after eight cycles not only has typical stem-loop structures but also includes known sequences of the linezolid binding site. The results of RNA footprinting show that the binding site of the heteroconjugate encompasses both stem and loop regions, suggesting that the possible binding site for linezolid is in the terminal loop. In addition, findings from application of a surface plasmon resonance assay clearly demonstrate that linezolid binds to selected hairpin RNA in a highly specific manner with a low millimolar affinity. The results suggest that heteroconjugates might represent a generally useful approach in studies aimed at uncovering loop-specific RNA binding ligands that would be otherwise difficult to identify owing to their weak affinities.
|
Binding affinity to Escherichia coli K12 stem-loop region L2-11 RNA aptamers using luminescence spectrometer by anisotropy technique
|
Escherichia coli
|
313.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Elucidation of the RNA target of linezolid by using a linezolid-neomycin B heteroconjugate and genomic SELEX.
Year : 2007
Volume : 15
Issue : 24
First Page : 7688
Last Page : 7695
Authors : Kim HJ, Kwon M, Yu J.
Abstract : A covalently modified heteroconjugate between linezolid and neomycin B leads to an enhanced and more specific binding affinity to hairpin RNA targets in comparison to neomycin B itself. This heteroconjugate was used as a lure to select linezolid-specific hairpin RNA from an Escherichia coli genome RNA. The selected RNA obtained after eight cycles not only has typical stem-loop structures but also includes known sequences of the linezolid binding site. The results of RNA footprinting show that the binding site of the heteroconjugate encompasses both stem and loop regions, suggesting that the possible binding site for linezolid is in the terminal loop. In addition, findings from application of a surface plasmon resonance assay clearly demonstrate that linezolid binds to selected hairpin RNA in a highly specific manner with a low millimolar affinity. The results suggest that heteroconjugates might represent a generally useful approach in studies aimed at uncovering loop-specific RNA binding ligands that would be otherwise difficult to identify owing to their weak affinities.
|
Binding affinity to Escherichia coli K12 stem-loop region L2-12 RNA aptamers using luminescence spectrometer by anisotropy technique
|
Escherichia coli
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Elucidation of the RNA target of linezolid by using a linezolid-neomycin B heteroconjugate and genomic SELEX.
Year : 2007
Volume : 15
Issue : 24
First Page : 7688
Last Page : 7695
Authors : Kim HJ, Kwon M, Yu J.
Abstract : A covalently modified heteroconjugate between linezolid and neomycin B leads to an enhanced and more specific binding affinity to hairpin RNA targets in comparison to neomycin B itself. This heteroconjugate was used as a lure to select linezolid-specific hairpin RNA from an Escherichia coli genome RNA. The selected RNA obtained after eight cycles not only has typical stem-loop structures but also includes known sequences of the linezolid binding site. The results of RNA footprinting show that the binding site of the heteroconjugate encompasses both stem and loop regions, suggesting that the possible binding site for linezolid is in the terminal loop. In addition, findings from application of a surface plasmon resonance assay clearly demonstrate that linezolid binds to selected hairpin RNA in a highly specific manner with a low millimolar affinity. The results suggest that heteroconjugates might represent a generally useful approach in studies aimed at uncovering loop-specific RNA binding ligands that would be otherwise difficult to identify owing to their weak affinities.
|
Binding affinity to A-site RNA
|
None
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and implementation of an ribonucleic acid (RNA) directed fragment library.
Year : 2009
Volume : 52
Issue : 12
First Page : 3753
Last Page : 3761
Authors : Bodoor K, Boyapati V, Gopu V, Boisdore M, Allam K, Miller J, Treleaven WD, Weldeghiorghis T, Aboul-ela F.
Abstract : The design of RNA binding ligands is complicated by issues of specificity, target flexibility, and the tractability of known RNA inhibitors toward chemical derivitization. To address these difficulties, an RNA-directed fragment compound library is presented. We began with an analysis of 120 small molecules with reported RNA-binding activity. Calculated physical and chemical properties for the RNA ligands are comparable to those of ligands for established protein drug targets. To ensure that our library contained RNA-binding functionalities that might not be detected by the above comparisons, 114 fragment compounds were purchased on the basis of similarity to substructures of RNA ligands. Five "hits" were identified for the decoding site from the bacterial ribosome by NMR. These included fragments derived from A-site binding ligands but also compounds not previously identified as A-site binders. Hits generated in this manner can be used to probe the interaction surface of RNA and its conformational plasticity, facilitating structure-based optimization.
|
Antibacterial activity against Klebsiella pneumoniae ATCC 700603
|
Klebsiella pneumoniae
|
0.6
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Discovery of Trp-His and His-Arg analogues as new structural classes of short antimicrobial peptides.
Year : 2009
Volume : 52
Issue : 23
First Page : 7421
Last Page : 7431
Authors : Sharma RK, Reddy RP, Tegge W, Jain R.
Abstract : Naturally occurring antimicrobial peptides contain a large number of amino acid residues, which limits their clinical applicability. In search of short antimicrobial peptides, which represent a possible alternative for lead structures to fight antibiotic resistant microbial infections, a series of synthetic peptide analogues based on Trp-His and His-Arg structural frameworks have been prepared and found to be active against several Gram-negative and Gram-positive bacterial strains as well as against a fungal strain with MIC values of the most potent structures in the range of 5-20 microg/mL ((IC(50) in the range of 1-5 microg/mL). The synthesized peptides showed no cytotoxic effect in an MTT assay up to the highest test concentration of 200 microg/mL. A combination of small size, presence of unnatural amino acids, high antimicrobial activity, and absence of cytotoxicity reveals the synthesized Trp-His and His-Arg analogues as promising candidates for novel antimicrobial therapeutics.
|
Inhibition of protein synthesis in Pseudomonas aeruginosa ATCC 27853 assessed as decrease in incorporation of L-[4,5-3H]leucine at MIC by liquid scintillation counter relative to control
|
Pseudomonas aeruginosa
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antimicrobial evaluation of amphiphilic neamine derivatives.
Year : 2010
Volume : 53
Issue : 1
First Page : 119
Last Page : 127
Authors : Baussanne I, Bussière A, Halder S, Ganem-Elbaz C, Ouberai M, Riou M, Paris JM, Ennifar E, Mingeot-Leclercq MP, Décout JL.
Abstract : The aminoglycoside antibiotics bind to the 16S bacterial rRNA and disturb the protein synthesis. One to four hydroxyl functions of the small aminoglycoside neamine were capped with phenyl, naphthyl, pyridyl, or quinolyl rings. The 3',4'- (6), 3',6- (7a), and the 3',4',6- (10a) 2-naphthylmethylene derivatives appeared to be active against sensitive and resistant Staphylococcus aureus strains. 10a also showed marked antibacterial activities against Gram (-) bacteria, including strains expressing enzymes modifying aminoglycosides, efflux pumps, or rRNA methylases. 7a and 10a revealed a weak and aspecific binding to a model bacterial 16S rRNA. Moreover, as compared to neomycin B, 10a showed a lower ability to decrease (3)H leucine incorporation into proteins in Pseudomonas aeruginosa. All together, our results suggest that the 3',4',6-tri-2-naphthylmethylene neamine derivative 10a should act against Gram (-) bacteria through a mechanism different from inhibition of protein synthesis, probably by membrane destabilization.
|
Inhibition of protein synthesis in Pseudomonas aeruginosa ATCC 27853 assessed as decrease in incorporation of L-[4,5-3H]leucine at 10 times MIC by liquid scintillation counter relative to control
|
Pseudomonas aeruginosa
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antimicrobial evaluation of amphiphilic neamine derivatives.
Year : 2010
Volume : 53
Issue : 1
First Page : 119
Last Page : 127
Authors : Baussanne I, Bussière A, Halder S, Ganem-Elbaz C, Ouberai M, Riou M, Paris JM, Ennifar E, Mingeot-Leclercq MP, Décout JL.
Abstract : The aminoglycoside antibiotics bind to the 16S bacterial rRNA and disturb the protein synthesis. One to four hydroxyl functions of the small aminoglycoside neamine were capped with phenyl, naphthyl, pyridyl, or quinolyl rings. The 3',4'- (6), 3',6- (7a), and the 3',4',6- (10a) 2-naphthylmethylene derivatives appeared to be active against sensitive and resistant Staphylococcus aureus strains. 10a also showed marked antibacterial activities against Gram (-) bacteria, including strains expressing enzymes modifying aminoglycosides, efflux pumps, or rRNA methylases. 7a and 10a revealed a weak and aspecific binding to a model bacterial 16S rRNA. Moreover, as compared to neomycin B, 10a showed a lower ability to decrease (3)H leucine incorporation into proteins in Pseudomonas aeruginosa. All together, our results suggest that the 3',4',6-tri-2-naphthylmethylene neamine derivative 10a should act against Gram (-) bacteria through a mechanism different from inhibition of protein synthesis, probably by membrane destabilization.
|
Binding affinity to RNA by RNA fluorescence assay
|
None
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Second generation analogs of rigid 6,7-spiro scaffolds targeting the bacterial ribosome.
Year : 2010
Volume : 20
Issue : 24
First Page : 7488
Last Page : 7492
Authors : Stathakis CI, Mavridis I, Kythreoti G, Papakyriakou A, Katsoulis IA, Cottin T, Anastasopoulou P, Vourloumis D.
Abstract : Previous work from our group described the synthesis and biological evaluation of new rigid, 6,6- and 6,7-spiro aminoglycosidic scaffolds targeting the bacterial ribosome. Herein we describe an improved synthetic protocol for their construction, and extend our study by further amino-functionalization of their 6,7-spiro analogs. The synthetic strategy, preparation and evaluation of some representative examples are reported.
|
Binding affinity to Escherichia coli ribosome assessed as inhibition of transcription-translational activity by luciferase assay
|
Escherichia coli
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Second generation analogs of rigid 6,7-spiro scaffolds targeting the bacterial ribosome.
Year : 2010
Volume : 20
Issue : 24
First Page : 7488
Last Page : 7492
Authors : Stathakis CI, Mavridis I, Kythreoti G, Papakyriakou A, Katsoulis IA, Cottin T, Anastasopoulou P, Vourloumis D.
Abstract : Previous work from our group described the synthesis and biological evaluation of new rigid, 6,6- and 6,7-spiro aminoglycosidic scaffolds targeting the bacterial ribosome. Herein we describe an improved synthetic protocol for their construction, and extend our study by further amino-functionalization of their 6,7-spiro analogs. The synthetic strategy, preparation and evaluation of some representative examples are reported.
|
Inhibition of rat phospholipase C
|
Rattus norvegicus
|
7.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
Year : 2010
Volume : 18
Issue : 21
First Page : 7675
Last Page : 7699
Authors : Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K.
Abstract : Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
|
Inhibition of HIV1 TAR RNA
|
Human immunodeficiency virus 1
|
417.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Recognition of HIV TAR RNA by triazole linked neomycin dimers.
Year : 2011
Volume : 21
Issue : 16
First Page : 4788
Last Page : 4792
Authors : Kumar S, Arya DP.
Abstract : A series of neomycin dimers have been synthesized using 'click chemistry' with varying linker functionality and length to target the TAR RNA region of HIV virus. TAR (trans activation response) RNA region, a 59 base pair stem loop structure located at 5'-end of all nascent HIV-1 transcripts interacts with a key regulatory protein, Tat, and necessitates the replication of HIV-1 virus. Neomycin, an aminosugar, has been shown to exhibit more than one binding site with HIV TAR RNA. Multiple TAR binding sites of neomycin prompted us to design and synthesize a small library of neomycin dimers using click chemistry. The binding between neomycin dimers and HIV TAR RNA was characterized using spectroscopic techniques including FID (Fluorescent Intercalator Displacement) titration and UV-thermal denaturation. UV thermal denaturation studies demonstrate that neomycin dimer binding increase the melting temperature (T(m)) of the HIV TAR RNA up to 10°C. Ethidium bromide displacement titrations revealed nanomolar IC(50) between neomycin dimers and HIV TAR RNA, whereas with neomycin, a much higher IC(50) in the micromolar range is observed.
|
Binding affinity to human pre-hsa-mir-155 miRNA assessed as inhibition of dicer-catalysed (33P)-labelled pre-miRNA processing at 1 mM after 1 hr by PAGE analysis
|
Homo sapiens
|
10.0
%
|
|
Binding affinity to human pre-hsa-mir-155 miRNA assessed as inhibition of dicer-catalysed (33P)-labelled pre-miRNA processing at 1 mM after 1 hr by PAGE analysis
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pre-microRNA binding aminoglycosides and antitumor drugs as inhibitors of Dicer catalyzed microRNA processing.
Year : 2012
Volume : 22
Issue : 4
First Page : 1709
Last Page : 1711
Authors : Maiti M, Nauwelaerts K, Herdewijn P.
Abstract : Over-expressions of miRNAs are being increasingly linked with many diseases including different types of cancer. In this study, the role of some known small molecular therapeutics has been investigated for their ability to bind with the pre-miRNA target (hsa-mir-155) and thereby to interfere with the Dicer catalyzed miRNA processing. Potential binding and inhibition effects have been demonstrated by some of these analogs. They can be used as leads for further development of potent small molecular miRNA-antagonists.
|
Inhibition of TRPV1-mediated membrane currents in human DRG neurons
|
Homo sapiens
|
400.0
nM
|
|
Journal : MedChemComm
Title : Scaffold-hopping from aminoglycosides to small synthetic inhibitors of bacterial protein biosynthesis using a pseudoreceptor model
Year : 2011
Volume : 2
Issue : 3
First Page : 181
Last Page : 184
Authors : Urbanek DA, Proschak E, Tanrikulu Y, Becker S, Karas M, Schneider G
|
Inhibition of pre-miR-372 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
60.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of pre-miR-373 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
60.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of pre-miR-17 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
60.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of pre-miR-21 (unknown origin) cleavage assessed as reduction of oncogenic microRNAs biogenesis at 200 uM by measuring fluorescence every minute for 5 hrs using 5'-FAM,3'-dabcyl-pre-miRNA beacons by FRET assay in presence of recombinant Dicer
|
Not specified
|
60.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting.
Year : 2015
Volume : 23
Issue : 17
First Page : 5334
Last Page : 5344
Authors : Tran TP, Vo DD, Di Giorgio A, Duca M.
Abstract : MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
|
Inhibition of ethidium bromide binding to r(CGCAAAUUUGCG)2 RNA (unknown origin) at 1:1 ratio of ligand:RNA measured after 5 mins by fluorescent intercalator displacement assay relative to control
|
Not specified
|
20.4
%
|
|
Journal : Bioorg Med Chem Lett
Title : Linker dependent intercalation of bisbenzimidazole-aminosugars in an RNA duplex; selectivity in RNA vs. DNA binding.
Year : 2016
Volume : 26
Issue : 24
First Page : 5989
Last Page : 5994
Authors : Ranjan N, Arya DP.
Abstract : Neomycin and Hoechst 33258 are two well-known nucleic acid binders that interact with RNA and DNA duplexes with high affinities respectively. In this manuscript, we report that covalent attachment of bisbenzimidazole unit derived from Hoechst 33258 to neomycin leads to intercalative binding of the bisbenzimidazole unit (oriented at 64-74° with respected to the RNA helical axis) in a linker length dependent manner. The dual binding and intercalation of conjugates were supported by thermal denaturation, CD, LD and UV-Vis absorption experiments. These studies highlight the importance of linker length in dual recognition by conjugates, for effective RNA recognition, which can lead to novel ways of recognizing RNA structures. Additionally, the ligand library screens also identify DNA and RNA selective compounds, with compound 9, containing a long linker, showing a 20.3°C change in RNA duplex Tm with only a 13.0°C change in Tm for the corresponding DNA duplex. Significantly, the shorter linker in compound 3 shows almost the reverse trend, a 23.8°C change in DNA Tm, with only a 9.1°C change in Tm for the corresponding RNA duplex.
|
Displacement of F-NEO from Escherichia coli rRNA-A site after 10 to 20 mins by fluorescence assay
|
Escherichia coli
|
87.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates.
Year : 2019
Volume : 163
First Page : 381
Last Page : 393
Authors : Story S, Skriba MJ, Maiti K, Nihar Ranjan, Degtyareva NN, Green KD, Khodaverdian V, Oyelere AK, Garneau-Tsodikova S, Arya DP.
Abstract : The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.
|
Displacement of F-NEO from human cytosolic rRNA-A site after 10 to 20 mins by fluorescence assay
|
Homo sapiens
|
76.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates.
Year : 2019
Volume : 163
First Page : 381
Last Page : 393
Authors : Story S, Skriba MJ, Maiti K, Nihar Ranjan, Degtyareva NN, Green KD, Khodaverdian V, Oyelere AK, Garneau-Tsodikova S, Arya DP.
Abstract : The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.
|
Binding affinity to rRNA-A site in human MDA-MB-231 cells assessed as inhibition of protein translation
|
Homo sapiens
|
139.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates.
Year : 2019
Volume : 163
First Page : 381
Last Page : 393
Authors : Story S, Skriba MJ, Maiti K, Nihar Ranjan, Degtyareva NN, Green KD, Khodaverdian V, Oyelere AK, Garneau-Tsodikova S, Arya DP.
Abstract : The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.
|
Binding affinity to biotinylated pre-miRNA-21 (unknown origin) by SPR analysis
|
Not specified
|
100.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Tetracyclines as Inhibitors of Pre-microRNA Maturation: A Disconnection between RNA Binding and Inhibition.
Year : 2019
Volume : 10
Issue : 5
First Page : 816
Last Page : 821
Authors : Garner AL, Lorenz DA, Sandoval J, Gallagher EE, Kerk SA, Kaur T, Menon A.
Abstract : In a high-throughput screening campaign, we recently discovered the rRNA-binding tetracyclines, methacycline and meclocycline, as inhibitors of Dicer-mediated processing of microRNAs. Herein, we describe our biophysical and biochemical characterization of these compounds. Interestingly, although direct, albeit weak, binding to the pre-microRNA hairpins was observed, the inhibitory activity of these compounds was not due to RNA binding. Through additional biochemical and chemical studies, we revealed that metal chelation likely plays a principle role in their mechanism of inhibition. By exploring the activity of other known RNA-binding scaffolds, we identified additional disconnections between direct RNA interaction and inhibition of Dicer processing. Thus, the results presented within provide a valuable case study in the complexities of targeting RNA with small molecules, particularly with weak binding and potentially promiscuous scaffolds.
|
Binding affinity to 5'-fluorescein-tagged Escherichia coli ribosomal A site wt-bac duplex RNA incubated for 2 mins by fluorescence spectrophotometric analysis
|
Escherichia coli
|
1.0
nM
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Binding affinity to 5'-fluorescein-tagged human mitochondrial ribosome A site mutant duplex RNA incubated for 2 mins by fluorescence spectrophotometry analysis
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Binding affinity to 5'-fluorescein-tagged Escherichia coli ribosomal A site wt-bac duplex RNA assessed as conformational change in RNA by measuring decrease in fluorescence intensity incubated for 2 mins by fluorescence spectrophotometric analysis
|
Escherichia coli
|
20.0
%
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
Binding affinity to 5'-fluorescein-tagged bacterial ribosomal A site 27-nucleotide hairpin RNA construct by fluorescence analysis
|
Bacteria
|
5.0
nM
|
|
Journal : Bioorg Med Chem
Title : Use of a fluorescence assay to determine relative affinities of semisynthetic aminoglycosides to small RNAs representing bacterial and mitochondrial A sites.
Year : 2019
Volume : 27
Issue : 22
First Page : 115121
Last Page : 115121
Authors : Waduge P, Sati GC, Crich D, Chow CS.
Abstract : The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.52
%
|
|
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
|
-0.07
%
|
|
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
|
-0.07
%
|
|
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.
|
Ototoxicity against C57BL/6 mouse cochlea hair cells assessed as reduction in cell viability at 0.1 mM incubated for 23 hrs by FITC-phalloidin staining-based assay
|
Mus musculus
|
20.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : The relationship between the structure and toxicity of aminoglycoside antibiotics.
Year : 2020
Volume : 30
Issue : 13
First Page : 127218
Last Page : 127218
Authors : Jospe-Kaufman M, Siomin L, Fridman M.
Abstract : Aminoglycoside antibiotics, used to treat persistent gram-negative infections, tuberculosis, and life-threatening infections in neonates and patients with cystic fibrosis, can infer acute kidney injury and irreversible hearing loss. The full repertoire of cellular targets and processes leading to the toxicity of aminoglycosides is not fully resolved, making it challenging to devise rational directions to circumvent their adverse effects. As a result, there has been very limited effort to rationally address the issue of aminoglycoside-induced toxicity. Here we provide an overview of the reported effects of aminoglycosides on cells of the inner ear and on kidney tubular epithelial cells. We describe selected examples for structure-toxicity relationships established by evaluation of both natural and semisynthetic aminoglycosides. The various assays and models used to evaluate these antibiotics and recent progress in development of safer aminoglycoside antibiotics are discussed.
