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- Title
Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study.
- Authors
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
- Abstract
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.
- Subjects
REVERSE transcriptase; DRUG resistance; NON-nucleoside reverse transcriptase inhibitors; HIV; EFAVIRENZ; ANGIOTENSIN I
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 2, p1215
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24021215