Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 190, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112085
Keywords
HIV-1; CA protein; Phenylalanine derivatives; 1,2,3-Triazole; SPR assay; MD simulation
Categories
Funding
- National Natural Science Foundation of China (NSFC) [81273354, 81573347]
- Key Project of NSFC for International Cooperation [81420108027]
- Young Scholars Program of Shandong University (YSPSDU) [2016WLJH32]
- Fundamental Research Funds of Shandong University [2017JC006]
- Key research and development project of Shandong Province [20170CGC1401, 2019JZZY021011]
- Major Project of Science and Technology of Shandong Province [2015ZDJS04001]
- NIH [RO1GM125396, R01A1150491, T32-MH079785]
Ask authors/readers for more resources
HIV-1 CA is involved in different stages of the viral replication cycle, performing essential roles in both early (uncoating, reverse transcription, nuclear import, integration) and late events (assembly). Recent efforts have demonstrated HIV-1 CA protein as a prospective therapeutic target for the development of new antivirals. The most extensively studied CA inhibitor, PF-3450074 (PF-74, discovered by Pfizer), that targets an inter-protomer pocket within the CA hexamer. Herein we reported the design, synthesis, and biological evaluation of a series of 4-phenyl-IH-1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors based on PF-74 scaffold. Most of the analogues demonstrated potent antiviral activities, among them, the anti-HIV-1 activity of 6a-9 (EC50 = 3.13 AM) is particularly prominent. The SPR binding assay of selected compounds (6a-9, 6a-10, 5b) suggested direct and effective interaction with recombinant CA proteins. The mechanism of action studies also demonstrated that 6a-9 displays the effects in both the early and late stages of HIV-1 replication. To explore the potential binding mode of the here presented analogues, 6a-9 was analyzed by MD simulation to predict its binding to the active site of HIV-1 CA monomer. In conclusion, this novel series of antivirals can serve as a starting point for the development of a new generation of HIV-1 treatment regimen and highlights the potentiality of CA as a therapeutic target. (C) 2020 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available