|
Potency evaluated against NNRTI-Resistant HIV-1 strain Gly190Ala
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Potency evaluated against NNRTI-Resistant HIV-1 strain Leu100Ile
|
Human immunodeficiency virus 1
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Potency evaluated against NNRTI-Resistant HIV-1 strain Lys103Asn
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Potency evaluated against NNRTI-Resistant HIV-1 strain Tyr181Cys
|
Human immunodeficiency virus 1
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Potency evaluated against NNRTI-Resistant HIV-1 strain Tyr188Leu
|
Human immunodeficiency virus 1
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Potency evaluated against NNRTI-Resistant HIV-1 strain Val106Ala
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Potency evaluated against wild type HIV-1 strain IIIB
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Year : 2004
Volume : 47
Issue : 10
First Page : 2550
Last Page : 2560
Authors : Das K, Clark AD, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E.
Abstract : Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
|
Inhibitory activity against 100I strain of HIV-I in MT-4 cells
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.
Year : 2001
Volume : 11
Issue : 17
First Page : 2235
Last Page : 2239
Authors : Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA.
Abstract : The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
|
Inhibitory activity against 103N strain and 181C strain of HIV-I in MT-4 cells
|
Human immunodeficiency virus 1
|
44.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.
Year : 2001
Volume : 11
Issue : 17
First Page : 2235
Last Page : 2239
Authors : Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA.
Abstract : The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
|
Inhibitory activity against 103N strain of HIV-I in MT-4 cells
|
Human immunodeficiency virus 1
|
4.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.
Year : 2001
Volume : 11
Issue : 17
First Page : 2235
Last Page : 2239
Authors : Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA.
Abstract : The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
|
Inhibitory activity against 181C strain of HIV-I in MT-4 cells
|
Human immunodeficiency virus 1
|
7.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.
Year : 2001
Volume : 11
Issue : 17
First Page : 2235
Last Page : 2239
Authors : Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA.
Abstract : The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
|
Inhibitory activity against 188L strain of HIV-I in MT-4 cells
|
Human immunodeficiency virus 1
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.
Year : 2001
Volume : 11
Issue : 17
First Page : 2235
Last Page : 2239
Authors : Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA.
Abstract : The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
|
Inhibitory activity against LAI strain of HIV-I in MT-4 cells
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.
Year : 2001
Volume : 11
Issue : 17
First Page : 2235
Last Page : 2239
Authors : Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Béthune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA.
Abstract : The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
|
Effective concentration against human immunodeficiency virus type 1 wild type strain
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1Y181C mutant strain
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 G190S mutant strain
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 L100I mutant strain
|
Human immunodeficiency virus 1
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 Y188L mutant strain
|
Human immunodeficiency virus 1
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration of the compound to inhibit HIV-1 mutant LAI replication in HIV-infected MT-4 cells
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 6
First Page : 1689
Last Page : 1696
Authors : De Corte BL.
|
Effective concentration against human immunodeficiency virus type 1 in K103N mutant strain
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration of the compound to inhibit HIV-1 mutant K103N replication in HIV-infected MT-4 cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 6
First Page : 1689
Last Page : 1696
Authors : De Corte BL.
|
Effective concentration of the compound to inhibit HIV-1 mutant L100I replication in HIV-infected MT-4 cells
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 6
First Page : 1689
Last Page : 1696
Authors : De Corte BL.
|
Effective concentration of the compound to inhibit HIV-1 mutant Y181C replication in HIV-infected MT-4 cells
|
Homo sapiens
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 6
First Page : 1689
Last Page : 1696
Authors : De Corte BL.
|
Effective concentration of the compound to inhibit HIV-1 mutant Y188L replication in HIV-infected MT-4 cells
|
Homo sapiens
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 6
First Page : 1689
Last Page : 1696
Authors : De Corte BL.
|
Effective concentration of the compound to inhibit HIV-1 mutant K103N+Y181C replication in HIV-infected MT-4 cells
|
Homo sapiens
|
44.0
nM
|
|
Journal : J. Med. Chem.
Title : From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2005
Volume : 48
Issue : 6
First Page : 1689
Last Page : 1696
Authors : De Corte BL.
|
Effective concentration against rhuman immunodeficiency virus type 1 K103N and Y181C mutant strains
|
Human immunodeficiency virus 1
|
54.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Antiviral activity against HIV1 NL4-3 infected in human TZM-bl cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.62
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2009
Volume : 19
Issue : 18
First Page : 5482
Last Page : 5485
Authors : Tian X, Qin B, Lu H, Lai W, Jiang S, Lee KH, Chen CH, Xie L.
Abstract : Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and drug-resistant HIV-1 strains.
|
Antiviral activity against HIV1 RTMDR1 infected in human TZM-bl cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.298
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2009
Volume : 19
Issue : 18
First Page : 5482
Last Page : 5485
Authors : Tian X, Qin B, Lu H, Lai W, Jiang S, Lee KH, Chen CH, Xie L.
Abstract : Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and drug-resistant HIV-1 strains.
|
Inhibition of RNA-dependent DNA polymerase activity of wild type HIV1 subtype B reverse transcriptase by filter-based filtration assay
|
Human immunodeficiency virus 1
|
19.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The M230L nonnucleoside reverse transcriptase inhibitor resistance mutation in HIV-1 reverse transcriptase impairs enzymatic function and viral replicative capacity.
Year : 2010
Volume : 54
Issue : 6
First Page : 2401
Last Page : 2408
Authors : Xu HT, Quan Y, Schader SM, Oliveira M, Bar-Magen T, Wainberg MA.
Abstract : The M230L mutation in HIV-1 reverse transcriptase (RT) is associated with resistance to first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The present study was designed to determine the effects of M230L on enzyme function, viral replication capacity (RC), and the extent to which M230L might confer resistance to the second-generation NNRTI etravirine (ETR) as well as to the first-generation NNRTIs efavirenz (EFV) and nevirapine (NVP). Phenotyping assays with TZM-bl cells confirmed that M230L conferred various degrees of resistance to each of the NNRTIs tested. Recombinant viruses containing M230L displayed an 8-fold decrease in RC compared to that of the parental wild-type (WT) virus. Recombinant HIV-1 WT and M230L mutant RT enzymes were purified; and both biochemical and cell-based phenotypic assays confirmed that M230L conferred resistance to each of EFV, NVP, and ETR. RT that contained M230L was also deficient in regard to each of minus-strand DNA synthesis, both DNA- and RNA-dependent polymerase activities, processivity, and RNase H activity, suggesting that this mutation contributes to diminished viral replication kinetics.
|
Inhibition of RNA-dependent DNA polymerase activity of HIV1 subtype B reverse transcriptase M230L mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
172.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The M230L nonnucleoside reverse transcriptase inhibitor resistance mutation in HIV-1 reverse transcriptase impairs enzymatic function and viral replicative capacity.
Year : 2010
Volume : 54
Issue : 6
First Page : 2401
Last Page : 2408
Authors : Xu HT, Quan Y, Schader SM, Oliveira M, Bar-Magen T, Wainberg MA.
Abstract : The M230L mutation in HIV-1 reverse transcriptase (RT) is associated with resistance to first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The present study was designed to determine the effects of M230L on enzyme function, viral replication capacity (RC), and the extent to which M230L might confer resistance to the second-generation NNRTI etravirine (ETR) as well as to the first-generation NNRTIs efavirenz (EFV) and nevirapine (NVP). Phenotyping assays with TZM-bl cells confirmed that M230L conferred various degrees of resistance to each of the NNRTIs tested. Recombinant viruses containing M230L displayed an 8-fold decrease in RC compared to that of the parental wild-type (WT) virus. Recombinant HIV-1 WT and M230L mutant RT enzymes were purified; and both biochemical and cell-based phenotypic assays confirmed that M230L conferred resistance to each of EFV, NVP, and ETR. RT that contained M230L was also deficient in regard to each of minus-strand DNA synthesis, both DNA- and RNA-dependent polymerase activities, processivity, and RNase H activity, suggesting that this mutation contributes to diminished viral replication kinetics.
|
Inhibition of DNA-dependent DNA polymerase activity of wild type HIV1 subtype B reverse transcriptase by gel-based primer extension assay
|
Human immunodeficiency virus 1
|
131.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The M230L nonnucleoside reverse transcriptase inhibitor resistance mutation in HIV-1 reverse transcriptase impairs enzymatic function and viral replicative capacity.
Year : 2010
Volume : 54
Issue : 6
First Page : 2401
Last Page : 2408
Authors : Xu HT, Quan Y, Schader SM, Oliveira M, Bar-Magen T, Wainberg MA.
Abstract : The M230L mutation in HIV-1 reverse transcriptase (RT) is associated with resistance to first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The present study was designed to determine the effects of M230L on enzyme function, viral replication capacity (RC), and the extent to which M230L might confer resistance to the second-generation NNRTI etravirine (ETR) as well as to the first-generation NNRTIs efavirenz (EFV) and nevirapine (NVP). Phenotyping assays with TZM-bl cells confirmed that M230L conferred various degrees of resistance to each of the NNRTIs tested. Recombinant viruses containing M230L displayed an 8-fold decrease in RC compared to that of the parental wild-type (WT) virus. Recombinant HIV-1 WT and M230L mutant RT enzymes were purified; and both biochemical and cell-based phenotypic assays confirmed that M230L conferred resistance to each of EFV, NVP, and ETR. RT that contained M230L was also deficient in regard to each of minus-strand DNA synthesis, both DNA- and RNA-dependent polymerase activities, processivity, and RNase H activity, suggesting that this mutation contributes to diminished viral replication kinetics.
|
Antiviral activity against HIV 1 subtype B harboring wild type reverse transcriptase infected in human TZM-bl cells assessed as inhibition of viral growth by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
0.91
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The M230L nonnucleoside reverse transcriptase inhibitor resistance mutation in HIV-1 reverse transcriptase impairs enzymatic function and viral replicative capacity.
Year : 2010
Volume : 54
Issue : 6
First Page : 2401
Last Page : 2408
Authors : Xu HT, Quan Y, Schader SM, Oliveira M, Bar-Magen T, Wainberg MA.
Abstract : The M230L mutation in HIV-1 reverse transcriptase (RT) is associated with resistance to first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The present study was designed to determine the effects of M230L on enzyme function, viral replication capacity (RC), and the extent to which M230L might confer resistance to the second-generation NNRTI etravirine (ETR) as well as to the first-generation NNRTIs efavirenz (EFV) and nevirapine (NVP). Phenotyping assays with TZM-bl cells confirmed that M230L conferred various degrees of resistance to each of the NNRTIs tested. Recombinant viruses containing M230L displayed an 8-fold decrease in RC compared to that of the parental wild-type (WT) virus. Recombinant HIV-1 WT and M230L mutant RT enzymes were purified; and both biochemical and cell-based phenotypic assays confirmed that M230L conferred resistance to each of EFV, NVP, and ETR. RT that contained M230L was also deficient in regard to each of minus-strand DNA synthesis, both DNA- and RNA-dependent polymerase activities, processivity, and RNase H activity, suggesting that this mutation contributes to diminished viral replication kinetics.
|
Antiviral activity against HIV 1 subtype B harboring reverse transcriptase M230L mutant infected in human TZM-bl cells assessed as inhibition of viral growth by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
5.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The M230L nonnucleoside reverse transcriptase inhibitor resistance mutation in HIV-1 reverse transcriptase impairs enzymatic function and viral replicative capacity.
Year : 2010
Volume : 54
Issue : 6
First Page : 2401
Last Page : 2408
Authors : Xu HT, Quan Y, Schader SM, Oliveira M, Bar-Magen T, Wainberg MA.
Abstract : The M230L mutation in HIV-1 reverse transcriptase (RT) is associated with resistance to first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The present study was designed to determine the effects of M230L on enzyme function, viral replication capacity (RC), and the extent to which M230L might confer resistance to the second-generation NNRTI etravirine (ETR) as well as to the first-generation NNRTIs efavirenz (EFV) and nevirapine (NVP). Phenotyping assays with TZM-bl cells confirmed that M230L conferred various degrees of resistance to each of the NNRTIs tested. Recombinant viruses containing M230L displayed an 8-fold decrease in RC compared to that of the parental wild-type (WT) virus. Recombinant HIV-1 WT and M230L mutant RT enzymes were purified; and both biochemical and cell-based phenotypic assays confirmed that M230L conferred resistance to each of EFV, NVP, and ETR. RT that contained M230L was also deficient in regard to each of minus-strand DNA synthesis, both DNA- and RNA-dependent polymerase activities, processivity, and RNase H activity, suggesting that this mutation contributes to diminished viral replication kinetics.
|
Antiviral activity against HIV-1 Bal infected in human TZM-bl cells after 7 days by RT assay
|
Human immunodeficiency virus 1
|
2.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human PM1 cells after 7 days by RT assay
|
Human immunodeficiency virus 1
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human monocyte derived macrophages after 7 days by RT assay
|
Human immunodeficiency virus 1
|
2.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 3B infected in human TZM-bl cells after 7 days by RT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 3B infected in human MT4 cells after 7 days by RT assay
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 RF infected in human PM1 cells after 7 days by RT assay
|
Human immunodeficiency virus 1
|
2.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human TZM-bl cells after 24 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
1.46
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human TZM-bl cells after 24 hrs by luciferase reporter gene assay in presence of 12.5% whole semen
|
Human immunodeficiency virus 1
|
1.75
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human TZM-bl cells after 24 hrs by luciferase reporter gene assay in presence of 12.5% cervical mucus
|
Human immunodeficiency virus 1
|
8.32
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 1 hr compound pretreated human ectocervical explant tissue assessed as inhibition of viral replication by RT-PCR
|
Human immunodeficiency virus 1
|
0.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 1 hr compound pretreated human ectocervical explant tissue assessed as inhibition of provirus formation at 1 nM by RT-PCR
|
Human immunodeficiency virus 1
|
99.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human PM1 cells assessed as inhibition of transmission of virus to premissive T cells
|
Human immunodeficiency virus 1
|
0.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in human PM1 cells assessed as inhibition of transmission of virus to premissive T cells at 10 uM
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 2 hrs 100 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 2 hrs 1000 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal measured after 2 days post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 2 hrs 10000 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal measured after 4 days post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 2 hrs 10000 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal measured after 6 days post compound removal
|
Human immunodeficiency virus 1
|
80.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 24 hrs 10 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 24 hrs 100 to 1000 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal measured after 2 days post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 24 hrs 100 to 1000 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal measured after 4 days post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 Bal infected in 24 hrs 100 to 1000 nM compound pretreated human ectocervical explant tissue assessed as prolonged inhibition of viral infection post compound removal measured after 6 days post compound removal
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 SF162 infected in hu-SCID mouse assessed as protection from viral infection at 225 uM
|
Human immunodeficiency virus type 1 (SF162 ISOLATE)
|
85.7
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Antiviral activity against HIV-1 SF162 infected in hu-SCID mouse assessed as protection from viral infection at 22.5 uM
|
Human immunodeficiency virus type 1 (SF162 ISOLATE)
|
78.6
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
Year : 2009
Volume : 53
Issue : 2
First Page : 487
Last Page : 495
Authors : Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R.
Abstract : Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.
|
Inhibition of RNA-dependent DNA polymerase activity of wild-type Human immunodeficiency virus 1 subtype B reverse transcriptase by filter-based filtration assay
|
Human immunodeficiency virus 1
|
370.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of Human immunodeficiency virus 1 subtype B reverse transcriptase G190A mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
517.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of Human immunodeficiency virus 1 subtype B reverse transcriptase Y181C mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
570.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of Human immunodeficiency virus 1 subtype B reverse transcriptase G190A-81C mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
404.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of Human immunodeficiency virus 1 subtype B reverse transcriptase DNA-dependent DNA polymerase activity by gel-based primer extension assay
|
Human immunodeficiency virus 1
|
322.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of DNA-dependent DNA polymerase activity of wild-type Human immunodeficiency virus 1 subtype B reverse transcriptase G190A mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
316.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of DNA-dependent DNA polymerase activity of wild-type Human immunodeficiency virus 1 subtype B reverse transcriptase Y181C mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
430.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Inhibition of DNA-dependent DNA polymerase activity of wild-type Human immunodeficiency virus 1 subtype B reverse transcriptase G190A-81C mutant by filter-based filtration assay
|
Human immunodeficiency virus 1
|
483.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity of wild-type Human immunodeficiency virus 1 isolate 5269 by cell based assay
|
Human immunodeficiency virus 1
|
0.0003
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity of wild-type Human immunodeficiency virus 1 isolate 5331 by cell based assay
|
Human immunodeficiency virus 1
|
0.004
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity of wild-type Human immunodeficiency virus 1 isolate 5512 by cell based assay
|
Human immunodeficiency virus 1
|
0.0105
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity of Human immunodeficiency virus 1 isolate 8116 harboring A98S, G190A mutation in reverse transcriptase by cell based assay
|
Human immunodeficiency virus 1
|
0.0001
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity of Human immunodeficiency virus 1 isolate 8117 harboring A98S, G190A mutation in reverse transcriptase by cell based assay
|
Human immunodeficiency virus 1
|
0.0002
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity of Human immunodeficiency virus 1 isolate 9225 harboring A98S, G190A mutation in reverse transcriptase by cell based assay
|
Human immunodeficiency virus 1
|
0.00035
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine.
Year : 2009
Volume : 53
Issue : 11
First Page : 4667
Last Page : 4672
Authors : Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA.
Abstract : Etravirine (ETR) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) active against common human immunodeficiency virus type 1 (HIV-1) drug-resistant strains. This study was designed to determine the extent to which each of the Y181C or G190A mutations in RT might confer resistance to ETR and other members of the NNRTI family of drugs. Recombinant HIV-1 RT enzymes containing either the Y181C or the G190A mutation, or both mutations in tandem, were purified. Both RNA- and DNA-dependent DNA polymerase assays were performed in order to determine the extent to which each of these mutations might confer resistance in cell-free biochemical assays against each of ETR, efavirenz, and nevirapine. Both the biochemical and the cell-based phenotypic assays confirmed the susceptibility of G190A-containing enzymes and viruses to ETR. The results of this study indicate that the G190A mutation is not associated with resistance to ETR.
|
Antiviral activity against X4 tropic HIV1 RF infected in human TZM-b1 cells after 2 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.84
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against X4 tropic HIV1 3B infected in human TZM-b1 cells after 2 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.53
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against R5 tropic HIV1 BaL infected in human TZM-b1 cells after 2 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against R5 tropic HIV1 YU.2 infected in human TZM-b1 cells after 2 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.15
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against X4 tropic HIV1 NL4.3 infected in human TZM-b1 cells after 2 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.37
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against R5 tropic HIV1 R8.BaL infected in human TZM-b1 cells after 2 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.19
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against X4 tropic HIV1 RF infected in human PBMC assessed as inhibition of p24 antigen production after 2 hrs by ELISA
|
Human immunodeficiency virus 1
|
1.48
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against HIV1 A17 harboring reverse transcriptase K103N, Y181C mutant infected in human TZM-b1 cells after 2 hrs by luciferase assays
|
Human immunodeficiency virus 1
|
8.34
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against R5 tropic HIV1 YU.2 infected in human PBMC assessed as inhibition of p24 antigen production after 2 hrs by ELISA
|
Human immunodeficiency virus 1
|
1.11
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against X4 tropic HIV1 NL4.3 infected in human PBMC assessed as inhibition of p24 antigen production after 2 hrs by ELISA
|
Human immunodeficiency virus 1
|
1.15
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against R5 tropic HIV1 R8.BaL infected in human PBMC assessed as inhibition of p24 antigen production after 2 hrs by ELISA
|
Human immunodeficiency virus 1
|
1.09
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against wild type HIV1 BaL in human TZM-b1 cells after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs).
Year : 2011
Volume : 19
Issue : 20
First Page : 5924
Last Page : 5934
Authors : Venkatraj M, Ariën KK, Heeres J, Dirié B, Joossens J, Van Goethem S, Van der Veken P, Michiels J, Vande Velde CM, Vanham G, Lewi PJ, Augustyns K.
Abstract : In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.
|
Antiviral activity against wild type HIV1 VI829 infected in human TZM-b1 cells after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs).
Year : 2011
Volume : 19
Issue : 20
First Page : 5924
Last Page : 5934
Authors : Venkatraj M, Ariën KK, Heeres J, Dirié B, Joossens J, Van Goethem S, Van der Veken P, Michiels J, Vande Velde CM, Vanham G, Lewi PJ, Augustyns K.
Abstract : In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.
|
Antiviral activity against HIV1 BaL expressing reverse transcriptase V106A mutant infected in human TZM-bl cells after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
2.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs).
Year : 2011
Volume : 19
Issue : 20
First Page : 5924
Last Page : 5934
Authors : Venkatraj M, Ariën KK, Heeres J, Dirié B, Joossens J, Van Goethem S, Van der Veken P, Michiels J, Vande Velde CM, Vanham G, Lewi PJ, Augustyns K.
Abstract : In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.
|
Antiviral activity against HIV1 VI829 expressing reverse transcriptase Y181C mutant infected in human TZM-bl cells after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
10.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs).
Year : 2011
Volume : 19
Issue : 20
First Page : 5924
Last Page : 5934
Authors : Venkatraj M, Ariën KK, Heeres J, Dirié B, Joossens J, Van Goethem S, Van der Veken P, Michiels J, Vande Velde CM, Vanham G, Lewi PJ, Augustyns K.
Abstract : In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.
|
Antiviral activity against wild type HIV 1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.03
nM
|
|
Journal : J. Med. Chem.
Title : Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.
Year : 2011
Volume : 54
Issue : 8
First Page : 3091
Last Page : 3096
Authors : Rotili D, Tarantino D, Artico M, Nawrozkij MB, Gonzalez-Ortega E, Clotet B, Samuele A, Esté JA, Maga G, Mai A.
Abstract : Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.
|
Antiviral activity against multidrug-resistant HIV 1 IRLL98 harboring reverse transcriptase K101Q/Y181C/G190a mutant infected in human MT4 cells assessed as virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.
Year : 2011
Volume : 54
Issue : 8
First Page : 3091
Last Page : 3096
Authors : Rotili D, Tarantino D, Artico M, Nawrozkij MB, Gonzalez-Ortega E, Clotet B, Samuele A, Esté JA, Maga G, Mai A.
Abstract : Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.
|
Antiviral activity against HIV 1 harboring reverse transcriptase K103N mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.
Year : 2011
Volume : 54
Issue : 8
First Page : 3091
Last Page : 3096
Authors : Rotili D, Tarantino D, Artico M, Nawrozkij MB, Gonzalez-Ortega E, Clotet B, Samuele A, Esté JA, Maga G, Mai A.
Abstract : Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.
|
Antiviral activity against HIV 1 harboring reverse transcriptase Y181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.
Year : 2011
Volume : 54
Issue : 8
First Page : 3091
Last Page : 3096
Authors : Rotili D, Tarantino D, Artico M, Nawrozkij MB, Gonzalez-Ortega E, Clotet B, Samuele A, Esté JA, Maga G, Mai A.
Abstract : Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.
|
Antiviral activity against HIV 1 harboring reverse transcriptase Y188L mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
333.9
nM
|
|
Journal : J. Med. Chem.
Title : Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.
Year : 2011
Volume : 54
Issue : 8
First Page : 3091
Last Page : 3096
Authors : Rotili D, Tarantino D, Artico M, Nawrozkij MB, Gonzalez-Ortega E, Clotet B, Samuele A, Esté JA, Maga G, Mai A.
Abstract : Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.
Year : 2012
Volume : 55
Issue : 7
First Page : 3558
Last Page : 3562
Authors : Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Esté JA, Maga G, Mai A.
Abstract : The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.
|
Antiviral activity against HIV1 harboring reverse transcriptase K103N mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.
Year : 2012
Volume : 55
Issue : 7
First Page : 3558
Last Page : 3562
Authors : Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Esté JA, Maga G, Mai A.
Abstract : The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.
|
Antiviral activity against HIV1 harboring reverse transcriptase Y181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.
Year : 2012
Volume : 55
Issue : 7
First Page : 3558
Last Page : 3562
Authors : Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Esté JA, Maga G, Mai A.
Abstract : The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.
|
Antiviral activity against HIV1 harboring reverse transcriptase Y188L mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.
Year : 2012
Volume : 55
Issue : 7
First Page : 3558
Last Page : 3562
Authors : Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Esté JA, Maga G, Mai A.
Abstract : The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.
|
Antiviral activity against HIV1 Ba-L harboring reverse transcriptase V106A mutant
|
Human immunodeficiency virus 1
|
2.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents.
Year : 2012
Volume : 22
Issue : 23
First Page : 7174
Last Page : 7178
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Messagie J, Michiels J, Van der Veken P, Vanham G, Lewi PJ, Augustyns K.
Abstract : This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.
|
Antiviral activity against HIV1 harboring reverse transcriptase VI829/Y181C mutant
|
Human immunodeficiency virus 1
|
10.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents.
Year : 2012
Volume : 22
Issue : 23
First Page : 7174
Last Page : 7178
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Messagie J, Michiels J, Van der Veken P, Vanham G, Lewi PJ, Augustyns K.
Abstract : This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.
|
Antiviral activity against HIV1 harboring reverse transcriptase VI829 mutant
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents.
Year : 2012
Volume : 22
Issue : 23
First Page : 7174
Last Page : 7178
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Messagie J, Michiels J, Van der Veken P, Vanham G, Lewi PJ, Augustyns K.
Abstract : This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.
|
Antiviral activity against wild type HIV1 Ba-L
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents.
Year : 2012
Volume : 22
Issue : 23
First Page : 7174
Last Page : 7178
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Messagie J, Michiels J, Van der Veken P, Vanham G, Lewi PJ, Augustyns K.
Abstract : This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.
|
Antiviral activity against HIV1 infected in human TZM-b1 cells
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents.
Year : 2012
Volume : 22
Issue : 23
First Page : 7174
Last Page : 7178
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Messagie J, Michiels J, Van der Veken P, Vanham G, Lewi PJ, Augustyns K.
Abstract : This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase K103N/Y181C double mutant infected in human MT4 cells assessed as protection against virus-induced effect
|
Human immunodeficiency virus 1
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase Y181C mutant infected in human MT4 cells assessed as protection against virus-induced effect
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase K103N/Y181C double mutant infected in human MT2 cells assessed as protection against virus-induced effect by MTT assay
|
Human immunodeficiency virus 1
|
39.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against wild type HIV1 3B infected in human MT2 cells assessed as protection against virus-induced effect by MTT assay
|
Human immunodeficiency virus 1
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against wild type HIV1 3B infected in human MT4 cells assessed as protection against virus-induced effect
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase Y181C mutant infected in human MT2 cells assessed as protection against virus-induced effect by MTT assay
|
Human immunodeficiency virus 1
|
39.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against wild type HIV1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against efavirenz-resistant HIV1 harboring RT 100I, 103R, 179D, 225H mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against N119-sensitive HIV1 harboring Y181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against A17-sensitive HIV1 harboring 103N, 181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against zidovudine-resistant HIV1 harboring RT 67N, 70R, 215F, 219Q mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against MDR-resistant HIV1 harboring 41L, 74V, 106A, 215Y mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against saquinavir-resistant HIV1 infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against 6-[(3,5-Dimethylphenyl)fluoromethyl]-5-ethyl-1-{[[4-(3-hydroxyprop-1-ynyl)benzyl]oxy]methyl}pyrimidine-2,4(1H,3H)-dione-resistant HIV1 harboring RT 106I, 181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against MC1220-resistant HIV1 harboring RT 100I, 179D, 181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel fluoro analogues of MKC442 as microbicides.
Year : 2014
Volume : 57
Issue : 12
First Page : 5169
Last Page : 5178
Authors : Loksha YM, Pedersen EB, Loddo R, Sanna G, Collu G, Giliberti G, La Colla P.
Abstract : Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5-dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p-iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long-term assays with heavily infected MT-4 cells.
|
Antiviral activity against HIV1 infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.
Year : 2014
Volume : 22
Issue : 19
First Page : 5241
Last Page : 5248
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Dirié B, Lyssens S, Michiels J, Cos P, Lewi PJ, Vanham G, Maes L, Van der Veken P, Augustyns K.
Abstract : The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antiviral activity against HIV1 NL4.3 infected in human TZM-bl cells incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family.
Year : 2016
Volume : 59
Issue : 6
First Page : 2747
Last Page : 2759
Authors : Tintori C, Brai A, Dasso Lang MC, Deodato D, Greco AM, Bizzarri BM, Cascone L, Casian A, Zamperini C, Dreassi E, Crespan E, Maga G, Vanham G, Ceresola E, Canducci F, Ariën KK, Botta M.
Abstract : Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.
|
Antiviral activity against R5-tropic HIV1 subtype B BaL infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against nevirapine resistant R5-tropic HIV1 subtype C VI829 expressing reverse transcriptase Y181C mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against HIV1 NL4.3 expressing reverse transcriptase K103N mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
2.8
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against HIV1 NL4.3 expressing reverse transcriptase K103N-Y181C mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
92.0
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Inhibition of wild-type HIV1 3B reverse transcriptase
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.
Year : 2018
Volume : 158
First Page : 371
Last Page : 392
Authors : Gu SX, Lu HH, Liu GY, Ju XL, Zhu YY.
Abstract : HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
|
Inhibition of recombinant HIV1 reverse transcriptase L100I mutant
|
Human immunodeficiency virus 1
|
15.85
nM
|
|
Journal : Eur J Med Chem
Title : Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.
Year : 2018
Volume : 158
First Page : 371
Last Page : 392
Authors : Gu SX, Lu HH, Liu GY, Ju XL, Zhu YY.
Abstract : HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
|
Inhibition of recombinant HIV1 reverse transcriptase K103N mutant
|
Human immunodeficiency virus 1
|
3.981
nM
|
|
Journal : Eur J Med Chem
Title : Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.
Year : 2018
Volume : 158
First Page : 371
Last Page : 392
Authors : Gu SX, Lu HH, Liu GY, Ju XL, Zhu YY.
Abstract : HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
|
Inhibition of recombinant HIV1 reverse transcriptase Y181C mutant
|
Human immunodeficiency virus 1
|
7.943
nM
|
|
Journal : Eur J Med Chem
Title : Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.
Year : 2018
Volume : 158
First Page : 371
Last Page : 392
Authors : Gu SX, Lu HH, Liu GY, Ju XL, Zhu YY.
Abstract : HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
|
Inhibition of recombinant HIV1 reverse transcriptase Y188L mutant
|
Human immunodeficiency virus 1
|
39.81
nM
|
|
Journal : Eur J Med Chem
Title : Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.
Year : 2018
Volume : 158
First Page : 371
Last Page : 392
Authors : Gu SX, Lu HH, Liu GY, Ju XL, Zhu YY.
Abstract : HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
|
Inhibition of recombinant HIV1 reverse transcriptase K103N/Y181C double mutant
|
Human immunodeficiency virus 1
|
39.81
nM
|
|
Journal : Eur J Med Chem
Title : Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.
Year : 2018
Volume : 158
First Page : 371
Last Page : 392
Authors : Gu SX, Lu HH, Liu GY, Ju XL, Zhu YY.
Abstract : HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
|
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
|
18.69
%
|
|
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.
|
Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells after 48 hours by high content imaging
|
Homo sapiens
|
730.0
nM
|
|
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.
|
Antiviral activity against wild type HIV 1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.6
nM
|
|
Journal : J Med Chem
Title : Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones.
Year : 2019
Volume : 62
Issue : 2
First Page : 604
Last Page : 621
Authors : Nawrozkij MB, Forgione M, Yablokov AS, Lucidi A, Tomaselli D, Patsilinakos A, Panella C, Hailu GS, Kirillov IA, Badia R, Riveira-Muñoz E, Crespan E, Armijos Rivera JI, Cirilli R, Ragno R, Esté JA, Maga G, Mai A, Rotili D.
Abstract : Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
|
Antiviral activity against HIV-1 IRLL98 harboring reverse transcriptase M41L, D67N, Y181C, M184V, R211K, and T215Y mutants infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
6.0
nM
|
|
Journal : J Med Chem
Title : Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones.
Year : 2019
Volume : 62
Issue : 2
First Page : 604
Last Page : 621
Authors : Nawrozkij MB, Forgione M, Yablokov AS, Lucidi A, Tomaselli D, Patsilinakos A, Panella C, Hailu GS, Kirillov IA, Badia R, Riveira-Muñoz E, Crespan E, Armijos Rivera JI, Cirilli R, Ragno R, Esté JA, Maga G, Mai A, Rotili D.
Abstract : Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
|
Antiviral activity against HIV 1 harboring reverse transcriptase Y181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
12.0
nM
|
|
Journal : J Med Chem
Title : Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones.
Year : 2019
Volume : 62
Issue : 2
First Page : 604
Last Page : 621
Authors : Nawrozkij MB, Forgione M, Yablokov AS, Lucidi A, Tomaselli D, Patsilinakos A, Panella C, Hailu GS, Kirillov IA, Badia R, Riveira-Muñoz E, Crespan E, Armijos Rivera JI, Cirilli R, Ragno R, Esté JA, Maga G, Mai A, Rotili D.
Abstract : Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
|
Antiviral activity against HIV-1 harboring reverse transcriptase Y188L mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
330.0
nM
|
|
Journal : J Med Chem
Title : Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones.
Year : 2019
Volume : 62
Issue : 2
First Page : 604
Last Page : 621
Authors : Nawrozkij MB, Forgione M, Yablokov AS, Lucidi A, Tomaselli D, Patsilinakos A, Panella C, Hailu GS, Kirillov IA, Badia R, Riveira-Muñoz E, Crespan E, Armijos Rivera JI, Cirilli R, Ragno R, Esté JA, Maga G, Mai A, Rotili D.
Abstract : Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
|
Antiviral activity against HIV-1 harboring reverse transcriptase K103N mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
2.2
nM
|
|
Journal : J Med Chem
Title : Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones.
Year : 2019
Volume : 62
Issue : 2
First Page : 604
Last Page : 621
Authors : Nawrozkij MB, Forgione M, Yablokov AS, Lucidi A, Tomaselli D, Patsilinakos A, Panella C, Hailu GS, Kirillov IA, Badia R, Riveira-Muñoz E, Crespan E, Armijos Rivera JI, Cirilli R, Ragno R, Esté JA, Maga G, Mai A, Rotili D.
Abstract : Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
|
Antiviral activity against HIV-1 harboring reverse transcriptase K103N/Y181C double mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
54.0
nM
|
|
Journal : J Med Chem
Title : Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones.
Year : 2019
Volume : 62
Issue : 2
First Page : 604
Last Page : 621
Authors : Nawrozkij MB, Forgione M, Yablokov AS, Lucidi A, Tomaselli D, Patsilinakos A, Panella C, Hailu GS, Kirillov IA, Badia R, Riveira-Muñoz E, Crespan E, Armijos Rivera JI, Cirilli R, Ragno R, Esté JA, Maga G, Mai A, Rotili D.
Abstract : Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.54
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.09
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.571
%
|
|
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
|
2.1
%
|
|
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
|
3.15
%
|
|
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
|
-0.15
%
|
|
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
|
3.15
%
|
|
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
|
2.1
%
|
|
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
|
-0.15
%
|
|
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.
