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  3. Design, synthesis, and biological evaluation of dual-site HIV-1 inhibitors simultaneously targeting the NNRTI binding pocket and an adjacent site with favorable resistance profiles

Design, synthesis, and biological evaluation of dual-site HIV-1 inhibitors simultaneously targeting the NNRTI binding pocket and an adjacent site with favorable resistance profiles

  • Bioorg Chem. 2025 Sep:164:108924. doi: 10.1016/j.bioorg.2025.108924.
Xiangkai Ji 1,  Xiangyi Jiang 1,  Xing Huang 1,  Heng Gao 1,  Zhen Gao 1,  Ping Gao 2,  Erik De Clercq 3,  Christophe Pannecouque 4,  Dongwei Kang 5,  Peng Zhan 6,  Xinyong Liu 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, China.
  • 2 Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 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, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012 Jinan, China. Electronic address: kangdongwei@sdu.edu.cn.
  • 6 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, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012 Jinan, China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 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, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012 Jinan, China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 40886479 DOI: 10.1016/j.bioorg.2025.108924
Abstract

Given high mutation rate of HIV-1 and its impact on NNRTIs' efficacy, targeting novel binding pockets has emerged as a viable strategy to overcome the drug resistance. In this study, we designed and synthesized 26 novel "dual-site" HIV-1 inhibitors that simultaneously target two distinct sites on Reverse Transcriptase (RT): the classical non-nucleoside inhibitor binding pocket (NNIBP) and a newly identified NNRTIs-adjacent site (NNIAS). Antiviral evaluation demonstrated that all compounds possessed potent activity against the wild-type (WT) HIV-1 strain, with EC50 values ranging from 4.1 to 86 nM. Notably, 11× maintained potent activity against WT and seven clinically relevant HIV-1 mutant strains. ELISA confirmed its significant inhibitory effect on HIV-1 RT. Molecular docking further revealed the dual-binding mode of 11× and provided a mechanistic rationale for its activity against both WT and resistant strains. Collectively, 11× represents a promising dual-site HIV-1 Inhibitor for further development.

Keywords

Dual-site inhibitors; HIV-1 NNRTIs; Molecular docking; Rational drug design; Resistance profiles.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-178031
    NNIBP和NNIAS双位点HIV-1抑制剂
    HIV
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