Since its emergence in December 2019, SARS-CoV-2 has infected over 200 million people globally. SARS-CoV-2 spike (S) decorates the viral envelope and is responsible for facilitating viral entry into the host cell. To mediate membrane fusion, S must be proteolytically cleaved. For the closely related SARS-CoV S, cleavage at the host cell surface must be facilitated by the serine protease TMPRSS2. We demonstrated that SARS-CoV-2 S can facilitate fusion independent of TMPRSS2 and sought to identify other proteases capable of driving SARS-CoV-2 S-mediated fusion. We show that the ADAMs and MMP inhibitor GI 254023X is capable of substantially reducing SARS-CoV-2 S-mediated syncytium formation. Additionally, we identified MMP-9, a protein target of GI 254023X, as a host protease capable of enhancing SARS-CoV-2 lentivirus entry in HEK293T-ACE2 cells. These results implicate ADAM and MMP proteases, in particular MMP-9, as potential antiviral drug targets against COVID-19 pathogenesis.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/42771 |
| Date | 30 September 2021 |
| Creators | Phan, Alexandra |
| Contributors | Côté, Marceline |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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