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

• Published in: Antimicrobial agents and chemotherapy 2016-09, Vol.60 (12)
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01428-16

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.