International journal of molecular sciences · 2023
Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study.
СтатьяНазвание и аннотация: Перевод в очереди
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Zhou Zhenzhen, Meng Bairu, An Jiaqi, Zhao Fabao, Sun Yanying, Zeng Dan, Wang Wenna, Gao Shenghua, Xia Yu, Dun Caiyun, De Clercq Erik, Pannecouque Christophe, Zhan Peng, Kang Dongwei, Liu Xinyong
Аннотация
This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.