Publication date: Sep 27, 2024
Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (M or 3CL) for replication and assembly. Our previous research on M of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of M inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits M activity in vitro as well as in a cell-based M expression assay. Most importantly TX inhibited SARS-CoV-2 replication in ACE2 expressing HeLa cells. Biochemical analysis and kinetic assays were consistent with TX acting as a non-competitive inhibitor. By contrast, TX was a weaker inhibitor and modifier of C300S M, confirming a role for Cys300 in inhibition of WT M but also providing evidence for an additional Cys target. TX pivalate (TP), a prodrug for TX that was previously marketed as a nasal spray, also inhibited SARS-CoV-2 replication in HeLa-ACE2 cells at low micromolar ICs. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 infection.
| Concepts | Keywords |
|---|---|
| C300s | Ace2 |
| Chymotrypsin | Cov |
| Competitive | Cys300 |
| Coronaviruses | Identified |
| Vitro | Inhibited |
| Inhibition | |
| Inhibitor | |
| Main | |
| Modifier | |
| Nasal | |
| Protease | |
| Replication | |
| Sars | |
| Spray | |
| Tixocortol |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Tixocortol |
| pathway | KEGG | Viral replication |
| drug | DRUGBANK | Chymotrypsin |
| disease | IDO | replication |
| drug | DRUGBANK | L-Cysteine |
| disease | IDO | site |
| disease | IDO | cell |
| disease | IDO | assay |
| disease | IDO | role |
| disease | MESH | SARS-CoV-2 infection |
| pathway | REACTOME | SARS-CoV-2 Infection |