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

研究成果: ジャーナルへの寄稿学術論文査読

10 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号10664
ジャーナルScientific Reports
10
1
DOI
出版ステータス出版済み - 2020 12月 1

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