Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Haydar Bulut, Shin ichiro Hattori, Hiromi Aoki-Ogata, Hironori Hayashi, Debananda Das, Manabu Aoki, David A. Davis, Kalapala Venkateswara Rao, Prasanth R. Nyalapatla, Arun K. Ghosh, Hiroaki Mitsuya

Research output: Contribution to journalArticlepeer-review

Abstract

HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV’s scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PRWT) and highly-multi-PI-resistance-associated PRDRVRP51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier.

Original languageEnglish
Article number10664
JournalScientific reports
Volume10
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • General

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