Article ; Online: Calpain-2 mediates SARS-CoV-2 entry via regulating ACE2 levels.
2024 Volume 15, Issue 3, Page(s) e0228723
Abstract: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show ... ...
| Abstract | Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (M Importance: Many efforts in small-molecule screens have been made to counter SARS-CoV-2 infection by targeting the viral main protease, the major element that processes viral proteins after translation. Here, we discovered that calpain inhibitors further block SARS-CoV-2 infection in a main protease-independent manner. We identified the host cysteine protease calpain-2 as an important positive regulator of the cell surface levels of SARS-CoV-2 cellular receptor ACE2 and, thus, a facilitator of viral infection. By either pharmacological inhibition or genetic knockout of calpain-2, the SARS-CoV-2 binding to host cells is blocked and viral infection is decreased. Our findings highlight a novel mechanism of ACE2 regulation, which presents a potential new therapeutic target. Since calpain inhibitors also potently interfere with the viral main protease, our data also provide a mechanistic understanding of the potential use of calpain inhibitors as dual inhibitors (entry and replication) in the clinical setting of COVID-19 diseases. Our findings bring mechanistic insights into the cellular process of SARS-CoV-2 entry and offer a novel explanation to the mechanism of activities of calpain inhibitors. |
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| MeSH term(s) | Humans ; SARS-CoV-2 ; COVID-19 ; Calpain/metabolism ; Calpain/pharmacology ; Angiotensin-Converting Enzyme 2/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; Antiviral Agents/pharmacology ; Virus Internalization |
| Chemical Substances | spike protein, SARS-CoV-2 ; Calpain (EC 3.4.22.-) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Spike Glycoprotein, Coronavirus ; Antiviral Agents |
| Language | English |
| Publishing date | 2024-02-13 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2557172-2 |
| ISSN | 2150-7511 ; 2161-2129 |
| ISSN (online) | 2150-7511 |
| ISSN | 2161-2129 |
| DOI | 10.1128/mbio.02287-23 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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