TY - JOUR
T1 - GRL-079, a novel HIV-1 protease inhibitor, is extremely potent against multidrug-resistant HIV-1 variants and has a high genetic barrier against the emergence of resistant variants
AU - Delino, Nicole S.
AU - Aoki, Manabu
AU - Hayashi, Hironori
AU - Hattori, Shin ichiro
AU - Chang, Simon B.
AU - Takamatsu, Yuki
AU - Martyr, Cuthbert D.
AU - Das, Debananda
AU - Ghosh, Arun K.
AU - Mitsuya, Hiroaki
N1 - Funding Information:
This project was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; by grants for the promotion of AIDS research from the Ministry of Health, Welfare, and Labor of Japan; by grants from the Japan Agency for Medical Research and Development (AMED); by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT); by a grant from the National Center for Global Health and Medicine (NCGM) Research Institute (to H.M.); and by a grant from the National Institutes of Health (GM53386 to A.K.G.). This work was also supported in part by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science), funded by MEXT and AMED.
Funding Information:
This project was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; by grants for the promotion of AIDS research from the Ministry of Health, Welfare, and Labor of Japan; by grants from the Japan Agency for Medical Research and Development (AMED); by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT); by a grant from the National Center for Global Health and Medicine (NCGM) Research Institute (to H.M.); and by a grant from the National Institutes of Health (GM53386 to A.K.G.). This work was also supported in part by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science), funded by MEXT and AMED. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (https://hpc.nih.gov). Sanger sequencing was conducted at the CCR Genomics Core at the National Cancer Institute.
Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/5
Y1 - 2018/5
N2 - We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C-5 position of P2 tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2= cyclopropyl (Cp) (or isopropyl)-aminobenzothiazole (Abt) moiety. Their 50% effective concentrations (EC50s) were 2.5 to 30 nM against wild-type HIV-1NL4-3, 0.3 to 6.7 nM against HIV-2EHO, and 0.9 to 90 nM against laboratory-selected PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIVMDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV) (HIVDRVrp51), with EC50s of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined (amprenavir, atazanavir, lopinavir [LPV], and DRV) had virtually no activity (EC50s of >1,000 nM) against HIVDRVrp51. Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between Tp-THF modified at C-5 and Asp29/Asp30/Gly48 of wild-type protease, while the P2= Cp-Abt group forms strong hydrogen bonds with Asp30=. The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. For selection with LPV and DRV by use of a mixture of 11 HIVMDR strains (HIV11MIX), HIV11MIX became highly resistant to LPV and DRV over 13 to 32 and 32 to 41 weeks, respectively. However, for selection with GRL-079 and GRL-058, HIV11MIX failed to replicate at >0.08 μM and >0.2 μM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the P2 Tp-THF group modified at C-5 and the P2= Abt group contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1NL4-3 and a wide spectrum of HIVMDR strains.
AB - We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C-5 position of P2 tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2= cyclopropyl (Cp) (or isopropyl)-aminobenzothiazole (Abt) moiety. Their 50% effective concentrations (EC50s) were 2.5 to 30 nM against wild-type HIV-1NL4-3, 0.3 to 6.7 nM against HIV-2EHO, and 0.9 to 90 nM against laboratory-selected PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIVMDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV) (HIVDRVrp51), with EC50s of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined (amprenavir, atazanavir, lopinavir [LPV], and DRV) had virtually no activity (EC50s of >1,000 nM) against HIVDRVrp51. Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between Tp-THF modified at C-5 and Asp29/Asp30/Gly48 of wild-type protease, while the P2= Cp-Abt group forms strong hydrogen bonds with Asp30=. The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. For selection with LPV and DRV by use of a mixture of 11 HIVMDR strains (HIV11MIX), HIV11MIX became highly resistant to LPV and DRV over 13 to 32 and 32 to 41 weeks, respectively. However, for selection with GRL-079 and GRL-058, HIV11MIX failed to replicate at >0.08 μM and >0.2 μM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the P2 Tp-THF group modified at C-5 and the P2= Abt group contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1NL4-3 and a wide spectrum of HIVMDR strains.
KW - AIDS
KW - HIV-1
KW - Protease
KW - Protease inhibitors
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U2 - 10.1128/AAC.02060-17
DO - 10.1128/AAC.02060-17
M3 - Article
C2 - 29463535
AN - SCOPUS:85046007990
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 5
M1 - e02060-17
ER -