Journal article
Design, synthesis and structure-activity relationships of novel HIV capsid inhibitors with potent antiviral activities
European journal of medicinal chemistry, v 295, 117784
22 May 2025
PMID: 40424778
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 (EC
= 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 (EC
= 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.
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Details
- Title
- Design, synthesis and structure-activity relationships of novel HIV capsid inhibitors with potent antiviral activities
- Creators
- Dazhou Shi - Shandong UniversityShujing Xu - Shandong UniversityLin Sun - Shandong UniversityPrem Prakash Sharma - University of DelhiBrijesh Rathi - University of DelhiMei Wang - Shandong UniversityLinan Wu - Shandong UniversityXiangyi Jiang - Shandong UniversityErik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchXinyong Liu - Shandong UniversityAlexej Dick - Drexel UniversityPeng Zhan - Shandong University
- Publication Details
- European journal of medicinal chemistry, v 295, 117784
- Publisher
- Elsevier
- Number of pages
- 21
- Grant note
- Key Research and Development Program, Ministry of Science and Technology of the People's Republic of China: 2023YFC2606500 Shandong Laboratory Program: SYS202205 China Postdoctoral Science Foundation: 2024M761823 National Institute of Health: 800162, 900048 Coulter Translational Fund: 284247
The authors are supported by the Key Research and Development Program, Ministry of Science and Technology of the People's Republic of China (No. 2023YFC2606500) , and the Shandong Laboratory Program (No. SYS202205) , and the China Postdoctoral Science Foundation (No. 2024M761823) , and the National Institute of Health (No. 800162 and 900048) and the Coulter Translational Fund (No. 284247) .
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001501522800001
- Scopus ID
- 2-s2.0-105005846761
- Other Identifier
- 991022054303804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal