C-5-modified tetrahydropyrano-tetrahydofuran-derived protease inhibitors (PIs) exert potent inhibition of the replication of HIV-1 variants highly resistant to various PIs, including darunavir

Manabu Aoki, Hironori Hayashi, Ravikiran S. Yedidi, Cuthbert D. Martyr, Yuki Takamatsu, Hiromi Aoki-Ogata, Teruya Nakamura, Hirotomo Nakata, Debananda Das, Yuriko Yamagata, Arun K. Ghosh, Hiroaki Mitsuya

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100μM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRVRP51); the three compounds remained active against HIV-1DRVRP51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR.

Original languageEnglish
Pages (from-to)2180-2194
Number of pages15
JournalJournal of virology
Volume90
Issue number5
DOIs
Publication statusPublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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