2. Academic Validation
  3. Design, synthesis and structure-activity relationships of novel HIV capsid inhibitors with potent antiviral activities

Design, synthesis and structure-activity relationships of novel HIV capsid inhibitors with potent antiviral activities

  • Eur J Med Chem. 2025 Oct 5:295:117784. doi: 10.1016/j.ejmech.2025.117784.
Dazhou Shi 1,  Shujing Xu 1,  Lin Sun 1,  Prem Prakash Sharma 2,  Brijesh Rathi 2,  Mei Wang 1,  Linan Wu 1,  Xiangyi Jiang 1,  Erik De Clercq 3,  Christophe Pannecouque 4,  Xinyong Liu 5,  Alexej Dick 6,  Peng Zhan 7
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, Jinan, Shandong, PR China.
  • 2 Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, India.
  • 3 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
  • 4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium. Electronic address: christophe.pannecouque@kuleuven.be.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
  • 6 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: 249455362@qq.com.
PMID: 40424778 DOI: 10.1016/j.ejmech.2025.117784
Abstract

The HIV capsid (CA) protein is a highly promising target for anti-HIV treatment due to its critical role in viral replication. Based on the optimization of 11L guided by PF74, a series of novel HIV CA inhibitors targeting the NTD-CTD interface were identified, demonstrating potent inhibitory effects against both HIV-1 and HIV-2. Notably, compound IC-2b4 (EC50 = 0.08 ± 0.02 μM) exhibits twice the potency of 11L and three times that of PF74 against HIV-1. For HIV-2, IC-2a4 (EC50 = 0.01 ± 0.00 μM) demonstrates twice the efficacy of 11L and 221 times that of PF74. In mechanistic studies, IC-2b4 was shown to bind directly and stably to CA, exerting robust inhibitory effects during both the early and late stages of infection-a property also observed with IC-2b3. Molecular dynamics simulations revealed that IC-2b4 forms more extensive interactions with CA compared to PF74, thereby enhancing Antiviral activity. These novel Antiviral compounds collectively provide valuable insights into developing anti-HIV therapies and highlight the therapeutic potential of the CA protein as a drug target.

Keywords

Capsid inhibitor; HIV; NTD-CTD interface; Structure-activity relationships; Structure-based drug design.

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