Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro

作者全名："Mao, Binli; Le-Trilling, Vu Thuy Khanh; Wang, Kai; Mennerich, Denise; Hu, Jie; Zhao, Zhenyu; Zheng, Jiaxin; Deng, Yingying; Katschinski, Benjamin; Xu, Shilei; Zhang, Guiji; Cai, Xuefei; Hu, Yuan; Wang, Jianwei; Lu, Mengji; Huang, Ailong; Tang, Ni; Trilling, Mirko; Lin, Yong"

作者地址："[Mao, Binli; Wang, Kai; Hu, Jie; Zhao, Zhenyu; Zheng, Jiaxin; Deng, Yingying; Zhang, Guiji; Cai, Xuefei; Hu, Yuan; Huang, Ailong; Tang, Ni; Lin, Yong] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Chine, Chongqing 400016, Peoples R China; [Le-Trilling, Vu Thuy Khanh; Mennerich, Denise; Katschinski, Benjamin; Lu, Mengji; Trilling, Mirko] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany; [Xu, Shilei] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Gen Surg, Guangzhou, Peoples R China; [Wang, Jianwei] Chongqing Med Univ, Coll Basic Med, Dept Immunol, Chongqing, Peoples R China"

通信作者："Huang, AL; Tang, N; Lin, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Chine, Chongqing 400016, Peoples R China.; Trilling, M (通讯作者)，Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany."

来源：EMERGING MICROBES & INFECTIONS

ESI学科分类：MICROBIOLOGY

WOS号：WOS:000753674300001

JCR分区：Q1

影响因子：13.2

年份：2022

卷号：11

期号：1

开始页：483

结束页：497

文献类型：Article

关键词：Obatoclax; SARS-CoV-2; endocytosis; membrane fusion; MCL-1

摘要："Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)- expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as a clinical drug for the treatment of COVID-19."

基金机构："National Natural Science Foundation of China [82002131]; Natural Science Foundation Project of CQ CSTC [cstc2020jcyj-msxmX0081]; Key Scientific and Technological Innovation Project from Chongqing Municipal Education Commission [KJCXZD2020018]; Venture and Innovation Support Program for Chongqing Overseas Returnees [cx2019114]; COVID-19 Emergency Project from Chongqing Medical University [CQMUNCP0207]; Faculty of Medicine University of Duisburg-Essen; Stiftung Universitatsmedizin Essen; Kulturstiftung Essen; Deutsche Forschungsgemeinschaft (DFG) [RTG 1949/2, TR1208/1-1, TR1208/2-1]"

基金资助正文："Y.L. received funding from the National Natural Science Foundation of China [grant number 82002131], the Natural Science Foundation Project of CQ CSTC [grant number cstc2020jcyj-msxmX0081], Key Scientific and Technological Innovation Project [grant number KJCXZD2020018] from Chongqing Municipal Education Commission, the Venture and Innovation Support Program for Chongqing Overseas Returnees [grant number cx2019114], and the COVID-19 Emergency Project [grant number CQMUNCP0207] from Chongqing Medical University. M.T. received funding from Faculty of Medicine University of Duisburg-Essen, Stiftung Universitatsmedizin Essen, the Kulturstiftung Essen, and the Deutsche Forschungsgemeinschaft (DFG) [grant number RTG 1949/2], [grant number TR1208/1-1], [grant number TR1208/2-1]."