Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study.
Int J Mol Sci
; 24(2)2023 Jan 07.
Artigo
em Inglês
| MEDLINE | ID: covidwho-2216327
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.
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Bases de dados internacionais
Base de dados:
MEDLINE
Assunto principal:
HIV-1
/
Fármacos Anti-HIV
Idioma:
Inglês
Ano de publicação:
2023
Tipo de documento:
Artigo
País de afiliação:
Ijms24021215
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