2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2020 Mar 15;190:112085. doi: 10.1016/j.ejmech.2020.112085.
Lin Sun 1,  Tianguang Huang 1,  Alexej Dick 2,  Megan E Meuser 2,  Waleed A Zalloum 3,  Chin-Ho Chen 4,  Xiao Ding 1,  Ping Gao 1,  Simon Cocklin 5,  Kuo-Hsiung Lee 6,  Peng Zhan 7,  Xinyong Liu 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
  • 2 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
  • 3 Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.
  • 4 Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.
  • 5 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA. Electronic address: sc349@drexel.edu.
  • 6 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. Electronic address: khlee@unc.edu.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 32066010 DOI: 10.1016/j.ejmech.2020.112085
Abstract

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.

Keywords

1,2,3-Triazole; CA protein; HIV-1; MD simulation; Phenylalanine derivatives; SPR assay.

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