期刊
EMERGING MICROBES & INFECTIONS
卷 11, 期 1, 页码 483-497出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/22221751.2022.2026739
关键词
Obatoclax; SARS-CoV-2; endocytosis; membrane fusion; MCL-1
资金
- 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]
Obatoclax has been identified as an effective antiviral compound that can block SARS-CoV-2 entry by inhibiting endocytosis and membrane fusion. It shows potent activity against different SARS-CoV-2 variants and could be a potential clinical drug for COVID-19 treatment.
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.
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