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 (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Sun, L; Huang, T; Dick, A; Meuser, ME; Zalloum, WA; Chen, C-H; Ding, X; Gao, P; Cocklin, S; Lee, K-H; Zhan, P; Liu, X
Published Date
- March 15, 2020
Published In
Volume / Issue
- 190 /
Start / End Page
- 112085 -
PubMed ID
- 32066010
Pubmed Central ID
- PMC7053825
Electronic International Standard Serial Number (EISSN)
- 1768-3254
Digital Object Identifier (DOI)
- 10.1016/j.ejmech.2020.112085
Language
- eng
Conference Location
- France