skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

Abstract

We here report that GRL-10413, a novel non-peptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (EC 50: 0.00035 - 0.0018 μM) with minimal cytotoxicity (CC 50: 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1 NL4-3variants selected by up to 5 μM concentrations of atazanavir, lopinavir, or amprenavir (EC 50: 0.0021 - 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multi-drug-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 of APV. In addition, GRL-10413 showed a favorable central nervous system (CNS) penetration property as assessed with anin vitroblood 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 thatmore » GRL-10413 has desirable features for treating patients infected with wild-type and/or multi-drug-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.« less

Authors:
; ; ; ORCiD logo; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHFOREIGN
OSTI Identifier:
1333966
Resource Type:
Journal Article
Resource Relation:
Journal Name: Antimicrobial Agents and Chemotherapy; Journal Volume: 60; Journal Issue: 12
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Amano, Masayuki, Salcedo-Gómez, Pedro Miguel, Zhao, Rui, Yedidi, Ravikiran S., Das, Debananda, Bulut, Haydar, Delino, Nicole S., Reddy, Sheri Venkata, Ghosh, Arun K., and Mitsuya, Hiroaki. A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413. United States: N. p., 2016. Web. doi:10.1128/AAC.01428-16.
Amano, Masayuki, Salcedo-Gómez, Pedro Miguel, Zhao, Rui, Yedidi, Ravikiran S., Das, Debananda, Bulut, Haydar, Delino, Nicole S., Reddy, Sheri Venkata, Ghosh, Arun K., & Mitsuya, Hiroaki. A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413. United States. doi:10.1128/AAC.01428-16.
Amano, Masayuki, Salcedo-Gómez, Pedro Miguel, Zhao, Rui, Yedidi, Ravikiran S., Das, Debananda, Bulut, Haydar, Delino, Nicole S., Reddy, Sheri Venkata, Ghosh, Arun K., and Mitsuya, Hiroaki. Mon . "A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413". United States. doi:10.1128/AAC.01428-16.
@article{osti_1333966,
title = {A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413},
author = {Amano, Masayuki and Salcedo-Gómez, Pedro Miguel and Zhao, Rui and Yedidi, Ravikiran S. and Das, Debananda and Bulut, Haydar and Delino, Nicole S. and Reddy, Sheri Venkata and Ghosh, Arun K. and Mitsuya, Hiroaki},
abstractNote = {We here report that GRL-10413, a novel non-peptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (EC50: 0.00035 - 0.0018 μM) with minimal cytotoxicity (CC50: 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1NL4-3variants selected by up to 5 μM concentrations of atazanavir, lopinavir, or amprenavir (EC50: 0.0021 - 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multi-drug-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 of APV. In addition, GRL-10413 showed a favorable central nervous system (CNS) penetration property as assessed with anin vitroblood 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 multi-drug-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.},
doi = {10.1128/AAC.01428-16},
journal = {Antimicrobial Agents and Chemotherapy},
number = 12,
volume = 60,
place = {United States},
year = {Mon Sep 12 00:00:00 EDT 2016},
month = {Mon Sep 12 00:00:00 EDT 2016}
}