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Hiroaki Mitsuya - One of the best experts on this subject based on the ideXlab platform.
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a modified p1 moiety enhances in vitro antiviral activity against various multidrug resistant hiv 1 variants and in vitro central nervous System Penetration properties of a novel nonpeptidic protease inhibitor grl 10413
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Masayuki Amano, Pedro Miguel Salcedogomez, Arun K Ghosh, Hiroaki Mitsuya, Rui Zhao, Ravikiran S Yedidi, H Bulut, Nicole S Delino, Venkata Reddy SheriAbstract:ABSTRACT We report here that GRL-10413, a novel nonpeptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a hydroxyethylamine sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC 50 ] of 0.00035 to 0.0018 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC 50 ] = 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1 NL4-3 variants selected by use of atazanavir, lopinavir, or amprenavir (APV) at concentrations of up to 5 μM (EC 50 = 0.0021 to 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that against APV. In addition, GRL-10413 showed favorable central nervous System (CNS) Penetration properties as assessed with an in vitro blood-brain barrier (BBB) reconstruction System. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants, with favorable CNS Penetration capability, and that the newly modified P1 moiety may confer desirable features in designing novel anti-HIV-1 PIs.
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a novel tricyclic ligand containing nonpeptidic hiv 1 protease inhibitor grl 0739 effectively inhibits the replication of multidrug resistant hiv 1 variants and has a desirable central nervous System Penetration property in vitro
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Masayuki Amano, Yasushi Tojo, Pedro Miguel Salcedogomez, Garth L Parham, Prasanth R Nyalapatla, Debananda Das, Arun K Ghosh, Hiroaki MitsuyaAbstract:We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 μM). GRL-0739 blocked the infectivity and replication of HIV-1NL4-3 variants selected by concentrations of up to 5 μM ritonavir or atazanavir (EC50, 0.035 to 0.058 μM). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2ROD variant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous System (CNS) Penetration property, as assessed using a novel in vitro blood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS Penetration profiles.
Gilles Pialoux - One of the best experts on this subject based on the ideXlab platform.
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discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy
Clinical Infectious Diseases, 2010Co-Authors: Ana Canestri, Corinne Amiel, Franaeoisxavier Lescure, Stéphane Jaureguiberry, Antoine Moulignier, Roland Tubiana, Gilles Peytavin, Anne-geneviève Marcelin, Gilles PialouxAbstract:Objective. We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. Design. We retrospectively identified instances of central nervous System (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were 1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous System Penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE ≤1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. Conclusions. Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.
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discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy
Clinical Infectious Diseases, 2010Co-Authors: Ana Canestri, Corinne Amiel, Franaeoisxavier Lescure, Stéphane Jaureguiberry, Antoine Moulignier, Roland Tubiana, Gilles Peytavin, Anne-geneviève Marcelin, Gilles PialouxAbstract:Objective We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. Design We retrospectively identified instances of central nervous System (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were Results Eleven patients had experienced acute or subacute neurological symptoms. All but one patient had CSF pleocytosis and/or elevated protein levels. The median CSF HIV RNA level was 880 copies/mL (range, 558-12,885 copies/mL). Patients had been receiving stable combination antiretroviral therapy for a median of 13 months (range, 10-32 months). Eight of 11 patients had a plasma HIV RNA level 1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous System Penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE 1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. Conclusions Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.
Anne-geneviève Marcelin - One of the best experts on this subject based on the ideXlab platform.
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discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy
Clinical Infectious Diseases, 2010Co-Authors: Ana Canestri, Corinne Amiel, Franaeoisxavier Lescure, Stéphane Jaureguiberry, Antoine Moulignier, Roland Tubiana, Gilles Peytavin, Anne-geneviève Marcelin, Gilles PialouxAbstract:Objective. We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. Design. We retrospectively identified instances of central nervous System (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were 1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous System Penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE ≤1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. Conclusions. Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.
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discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy
Clinical Infectious Diseases, 2010Co-Authors: Ana Canestri, Corinne Amiel, Franaeoisxavier Lescure, Stéphane Jaureguiberry, Antoine Moulignier, Roland Tubiana, Gilles Peytavin, Anne-geneviève Marcelin, Gilles PialouxAbstract:Objective We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. Design We retrospectively identified instances of central nervous System (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were Results Eleven patients had experienced acute or subacute neurological symptoms. All but one patient had CSF pleocytosis and/or elevated protein levels. The median CSF HIV RNA level was 880 copies/mL (range, 558-12,885 copies/mL). Patients had been receiving stable combination antiretroviral therapy for a median of 13 months (range, 10-32 months). Eight of 11 patients had a plasma HIV RNA level 1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous System Penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE 1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. Conclusions Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.
Ana Canestri - One of the best experts on this subject based on the ideXlab platform.
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discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy
Clinical Infectious Diseases, 2010Co-Authors: Ana Canestri, Corinne Amiel, Franaeoisxavier Lescure, Stéphane Jaureguiberry, Antoine Moulignier, Roland Tubiana, Gilles Peytavin, Anne-geneviève Marcelin, Gilles PialouxAbstract:Objective. We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. Design. We retrospectively identified instances of central nervous System (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were 1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous System Penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE ≤1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. Conclusions. Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.
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discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy
Clinical Infectious Diseases, 2010Co-Authors: Ana Canestri, Corinne Amiel, Franaeoisxavier Lescure, Stéphane Jaureguiberry, Antoine Moulignier, Roland Tubiana, Gilles Peytavin, Anne-geneviève Marcelin, Gilles PialouxAbstract:Objective We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. Design We retrospectively identified instances of central nervous System (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were Results Eleven patients had experienced acute or subacute neurological symptoms. All but one patient had CSF pleocytosis and/or elevated protein levels. The median CSF HIV RNA level was 880 copies/mL (range, 558-12,885 copies/mL). Patients had been receiving stable combination antiretroviral therapy for a median of 13 months (range, 10-32 months). Eight of 11 patients had a plasma HIV RNA level 1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous System Penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE 1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. Conclusions Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.
Masayuki Amano - One of the best experts on this subject based on the ideXlab platform.
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a modified p1 moiety enhances in vitro antiviral activity against various multidrug resistant hiv 1 variants and in vitro central nervous System Penetration properties of a novel nonpeptidic protease inhibitor grl 10413
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Masayuki Amano, Pedro Miguel Salcedogomez, Arun K Ghosh, Hiroaki Mitsuya, Rui Zhao, Ravikiran S Yedidi, H Bulut, Nicole S Delino, Venkata Reddy SheriAbstract:ABSTRACT We report here that GRL-10413, a novel nonpeptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a hydroxyethylamine sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC 50 ] of 0.00035 to 0.0018 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC 50 ] = 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1 NL4-3 variants selected by use of atazanavir, lopinavir, or amprenavir (APV) at concentrations of up to 5 μM (EC 50 = 0.0021 to 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that against APV. In addition, GRL-10413 showed favorable central nervous System (CNS) Penetration properties as assessed with an in vitro blood-brain barrier (BBB) reconstruction System. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants, with favorable CNS Penetration capability, and that the newly modified P1 moiety may confer desirable features in designing novel anti-HIV-1 PIs.
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a novel tricyclic ligand containing nonpeptidic hiv 1 protease inhibitor grl 0739 effectively inhibits the replication of multidrug resistant hiv 1 variants and has a desirable central nervous System Penetration property in vitro
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Masayuki Amano, Yasushi Tojo, Pedro Miguel Salcedogomez, Garth L Parham, Prasanth R Nyalapatla, Debananda Das, Arun K Ghosh, Hiroaki MitsuyaAbstract:We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 μM). GRL-0739 blocked the infectivity and replication of HIV-1NL4-3 variants selected by concentrations of up to 5 μM ritonavir or atazanavir (EC50, 0.035 to 0.058 μM). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2ROD variant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous System (CNS) Penetration property, as assessed using a novel in vitro blood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS Penetration profiles.
