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

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机构: [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]Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China [3]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 [4]Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, KIZCUHK 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 [5]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
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关键词: HIV-1 Vif Antiviral PROTAC Vif protein degradation Molecular dynamics simulation

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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).Copyright © 2024 Elsevier Ltd. All rights reserved.

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出版当年[2023]版:
大类 | 4 区 医学
小类 | 2 区 有机化学 4 区 药物化学
最新[2023]版:
大类 | 4 区 医学
小类 | 2 区 有机化学 4 区 药物化学
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第一作者机构: [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]Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
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