2. Academic Validation
  3. Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors

Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors

  • Bioorg Med Chem. 2021 Oct 15;48:116414. doi: 10.1016/j.bmc.2021.116414.
Jing Li 1,  Xiangyi Jiang 1,  Alexej Dick 2,  Prem Prakash Sharma 3,  Chin-Ho Chen 4,  Brijesh Rathi 3,  Dongwei Kang 1,  Zhao Wang 1,  Xiangkai Ji 1,  Kuo-Hsiung Lee 5,  Simon Cocklin 6,  Xinyong Liu 7,  Peng Zhan 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 19102, USA.
  • 3 Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India.
  • 4 Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC 27710, USA.
  • 5 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
  • 6 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Electronic address: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 34562701 DOI: 10.1016/j.bmc.2021.116414
Abstract

The HIV-1 Capsid (CA) is considered as a promising target for the development of potent Antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and Antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 μM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 μM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.

Keywords

HIV-1 CA inhibitors; HIV-1 Capside Protein; PF-74 derivative; Scaffold Hopping.

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