Design, synthesis and biological evaluation of anti-HIV-1 Vif inhibitors based on prodrug strategy

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130351. doi: 10.1016/j.bmcl.2025.130351.
Weilin Wang  1 ,  Rui Deng  1 ,  Rong-Hua Luo  2 ,  Hongjia Zhang  1 ,  Dan Luo  3 ,  Shirui Wang  1 ,  Su Yu  1 ,  Xinyu Ma  1 ,  Chunlan Pu  4 ,  Yuanyuan Liu  1 ,  Qing Huang  1 ,  Liu-Meng Yang  2 ,  Yong-Tang Zheng  5 ,  Rui Li  6
Affiliations
  • 1. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Sichuan, Chengdu 610041, China.
  • 2. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China.
  • 3. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Sichuan, Chengdu 610041, China.; Department of pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 4. Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610504, China.
  • 5. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China. Electronic address: [email protected].
  • 6. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Sichuan, Chengdu 610041, China.. Electronic address: [email protected].
PMID: 40730252 DOI: 10.1016/j.bmcl.2025.130351
Abstract

In this work, we describe the design, synthesis, and biological evaluation of a series of novel dual-target prodrugs that simultaneously target HIV-1 viral Infection factors (Vif) and Reverse Transcriptase (RT). Among them, the two most effective compounds, A1 and A7, were found to inhibit HIV-1IIIB at nanomolar concentrations (EC50 = 8.1 nM, EC50 = 9.4 nM) in C8166 cells, which were 95 and 81 times higher than the parent drug 6 m, respectively, and 2.7 and 2.3 times higher than that of stavudine (d4T). The stability of compound A1 in the medium suggests that it can effectively release the parent drugs 6 m and stavudine with a half-life of 6 h, suggesting that it is a potential dual-target prodrug targeting HIV Vif and Reverse Transcriptase.

Keywords
Antiviral; Dual-target prodrug; HIV-1; Vif.
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