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Design, synthesis and structure-activity relationships of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as novel HIV-1 capsid inhibitors with promising antiviral activities
Journal article   Open access   Peer reviewed

Design, synthesis and structure-activity relationships of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as novel HIV-1 capsid inhibitors with promising antiviral activities

Lin Sun, Tianguang Huang, Alexej Dick, Megan E. Meuser, Waleed A. Zalloum, Chin-Ho Chen, Xiao Ding, Ping Gao, Simon Cocklin, Kuo-Hsiung Lee, …
European journal of medicinal chemistry, v 190, 112085
15 Mar 2020
DOI: https://doi.org/10.1016/j.ejmech.2020.112085
PMID: 32066010
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053825View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

1,2,3-Triazole CA protein HIV-1 MD simulation Phenylalanine derivatives SPR assay
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-1H-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 μM) 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. [Display omitted] •4-Phenyl-1H-1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors were first reported.•6a-9 showed the best anti-HIV-1 activity among this series.•6a-9 exhibited the dual-stage inhibitory activity like the lead PF-74.

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Domestic collaboration
International collaboration
Web of Science research areas
Chemistry, Medicinal
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