Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR  

作　　者：Jin-feng Cai Jia-sheng Zhou Zhuo-yue Meng Zi-qi Wu Jia-cong Zhao Hai-xiang Peng Xin-yu Liang Jun-jian Chen Pei-pei Wang Kai Deng 

机构地区：[1]Institute of Human Virology,Key Laboratory of Tropical Disease Control of Ministry of Education,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,510080,China [2]Department of Immunology and Microbiology,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,510080,China [3]Department of Infectious Diseases,the Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,510630,China [4]Advanced Medical Technology Center,The First Affiliated Hospital,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,510080,China

出　　处：《Acta Pharmacologica Sinica》2024年第8期1632-1643,共12页中国药理学报（英文版）

基　　金：supported by National Key R&D Program of China(2021YFC2301903);National Natural Science Foundation of China(32070159,82302514 to JFC);Science and Technology Projects of Guangdong Province of China(2021B1212030012);the Advanced Medical Technology Center Program of The First Affiliated Hospital of Sun Yat-sen University to KD;the Nurturing Program of Key Laboratory of Tropical Disease Control of Ministry of Education(SYSU)to JJC.

摘　　要：Despite the effectiveness of antiretroviral therapy(ART)in prolonging the lifespan of individuals infected with HIV-1,it does not offer a cure for acquired immunodeficiency syndrome(AIDS).The“block and lock”approach aims to maintain the provirus in a state of extended transcriptional arrest.By employing the“block and lock”strategy,researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART.The crux of this strategy lies in the utilization of latency-promoting agents(LPAs)that are suitable for impeding HIV-1 provirus transcription.However,previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients,underscoring the significance of identifying novel LPAs that yield substantial outcomes.In this study,we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs.We discovered ripretinib being an LPA candidate,which was validated and observed to hinder proviral activation in cell models harboring latent infections,as well as CD4^(+)T cells derived from infected patients.We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells,thereby suppressing the opening states of cellular chromatin.The results of this research offer a promising drug candidate for the implementation of the“block and lock”strategy in the pursuit of an HIV-1 cure.

关 键 词：HIV-1 block and lock latency-promoting agents ripretinib PI3K-AKT-mTOR 

分 类 号：R285[医药卫生—中药学]