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

Autor:	Mao B; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Le-Trilling VTK; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Wang K; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Mennerich D; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Hu J; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Zhao Z; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Zheng J; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Deng Y; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Katschinski B; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Xu S; Department of General Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China., Zhang G; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Cai X; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Hu Y; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Wang J; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China., Lu M; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Huang A; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Tang N; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China., Trilling M; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Lin Y; Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, People's Republic of China.
Jazyk:	angličtina
Zdroj:	Emerging microbes & infections [Emerg Microbes Infect] 2022 Dec; Vol. 11 (1), pp. 483-497.
DOI:	10.1080/22221751.2022.2026739
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu