2. Academic Validation
  3. Design, synthesis and biological evaluation of anti-HIV-1 Vif inhibitors based on prodrug strategy

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

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: Zhengyt@mail.kiz.ac.cn.
  • 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: lirui@scu.edu.cn.
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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