2. Academic Validation
  3. Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1

Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1

  • Bioorg Med Chem Lett. 2024 Jul 10:111:129880. doi: 10.1016/j.bmcl.2024.129880.
Dan Luo 1,  Ronghua Luo 2,  Weilin Wang 3,  Rui Deng 3,  Shirui Wang 3,  Xinyu Ma 3,  Chunlan Pu 4,  Yuanyuan Liu 3,  Hongjia Zhang 3,  Su Yu 3,  Qing Huang 3,  Liumeng Yang 2,  Yu Tong 5,  Yongtang Zheng 6,  Rui Li 7
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; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 2 Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, 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.
  • 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 West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, Sichuan Province, China. Electronic address: zisu_yu@163.com.
  • 6 Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. Electronic address: Zhengyt@mail.kiz.ac.cn.
  • 7 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: 38996941 DOI: 10.1016/j.bmcl.2024.129880
Abstract

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of Cancer, but the Antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the Antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 Ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based Antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

Keywords

Antiviral; HIV-1; Molecular dynamics simulation; PROTAC; Vif; Vif protein degradation.

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