Novel protease inhibitors containing C-5-modified bis-tetrahydrofuranylurethane and aminobenzothiazole as P2 and P2= ligands that exert potent antiviral activity against highly multidrug-resistant HIV-1 with a high genetic barrier against the emergence of drug resistance

Yuki Takamatsu, Manabu Aoki, Haydar Bulut, Debananda Das, Masayuki Amano, Venkata Reddy Sheri, Ladislau C. Kovari, Hironori Hayashi, Nicole S. Delino, Arun K. Ghosh, Hiroaki Mitsuya

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Combination antiretroviral therapy has achieved dramatic reductions in the mortality and morbidity in people with HIV-1 infection. Darunavir (DRV) represents a most efficacious and well-tolerated protease inhibitor (PI) with a high genetic barrier to the emergence of drug-resistant HIV-1. However, highly DRV-resistant variants have been reported in patients receiving long-term DRV-containing regimens. Here, we report three novel HIV-1 PIs (GRL-057-14, GRL-058-14, and GRL-059-14), all of which contain a P2-amino-substituted-bis-tetrahydrofuranylurethane (bis-THF) and a P2=-cyclopropyl-amino-benzothiazole (Cp-Abt). These PIs not only potently inhibit the replication of wild-type HIV-1 (50% effective concentration [EC50], 0.22 nM to 10.4 nM) but also inhibit multi-PI-resistant HIV-1 variants, including highly DRV-resistant HIVDRVRP51 (EC50, 1.6 nM to 30.7 nM). The emergence of HIV-1 variants resistant to the three compounds was much delayed in selection experiments compared to resistance to DRV, using a mixture of 11 highly multi-PI-resistant HIV-1 isolates as a starting HIV-1 population. GRL-057-14 showed the most potent anti-HIV-1 activity and greatest thermal stability with wild-type protease, and potently inhibited HIV-1 protease’s proteolytic activity (Ki value, 0.10 nM) among the three PIs. Structural models indicate that the C-5-iso-propylamino-bis-THF moiety of GRL-057-14 forms additional polar interactions with the active site of HIV-1 protease. Moreover, GRL-057-14’s P1-bis-fluoro-methylbenzene forms strong hydrogen bonding and effective van der Waals interactions. The present data suggest that the combination of C-5-aminoalkyl-bis-THF, P1-bis-fluoro-methylbenzene, and P2=-Cp-Abt confers highly potent activity against wild-type and multi-PI-resistant HIV strains and warrant further development of the three PIs, in particular, that of GRL-057-14, as potential therapeutic for HIV-1 infection and AIDS.

Original languageEnglish
Article numbere00372-19
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number8
DOIs
Publication statusPublished - 2019
Externally publishedYes

Keywords

  • AIDS
  • Human immunodeficiency virus
  • Multidrug resistance
  • Protease inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Novel protease inhibitors containing C-5-modified bis-tetrahydrofuranylurethane and aminobenzothiazole as P2 and P2= ligands that exert potent antiviral activity against highly multidrug-resistant HIV-1 with a high genetic barrier against the emergence of drug resistance'. Together they form a unique fingerprint.

Cite this