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.
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 [EC50] of 0.00035 to 0.0018 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC50] = 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1NL4-3variants selected by use of atazanavir, lopinavir, or amprenavir (APV) at concentrations of up to 5 μM (EC50= 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.
Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
Masayuki
0000-0003-0516-9502
M
Amano
Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
Pedro Miguel
PM
Salcedo-Gómez
Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
Rui
R
Zhao
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|Department of Pharmacology, GSL Medical College and General Hospital, Rajahmundry, Andhra Pradesh, India.
Ravikiran S
0000-0003-2755-1307
RS
Yedidi
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Debananda
D
Das
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Haydar
H
Bulut
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Nicole S
NS
Delino
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.
Venkata Reddy
VR
Sheri
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.
Arun K
AK
Ghosh
Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan hm21q@nih.gov.|Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
Hiroaki
H
Mitsuya
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects / Q000821:virology; D018360:Crystallography, X-Ray; D000069454:Darunavir / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects* / Q000235:genetics; D005021:Ethylamines / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D002219:Carbamates; D005021:Ethylamines; D005663:Furans; C000622534:GRL-10413; D017320:HIV Protease Inhibitors; D010455:Peptides; D013449:Sulfonamides; D061466:Lopinavir; C095108:amprenavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir