tetano
Editor, Senior Moderator
RSC Med Chem
. 2024 Sep 27.
doi: 10.1039/d4md00454j. Online ahead of print. Discovery of a nasal spray steroid, tixocortol, as an inhibitor of SARS-CoV-2 main protease and viral replication
David A Davis[SUP] 1 [/SUP], Ashwin Nair[SUP] 1 [/SUP], Yana Astter[SUP] 1 [/SUP], Emma Treco[SUP] 1 [/SUP], Brian Peyser[SUP] 2 [/SUP], Rick Gussio[SUP] 3 4 [/SUP], Tam Nguyen[SUP] 2 [/SUP], Brett Eaton[SUP] 5 [/SUP], Elena Postnikova[SUP] 5 [/SUP], Michael Murphy[SUP] 5 [/SUP], Prabha Shrestha[SUP] 1 [/SUP], Haydar Bulut[SUP] 1 [/SUP], Shin-Ichiro Hattorri[SUP] 6 [/SUP], Hiroaki Mitsuya[SUP] 1 6 [/SUP], Robert Yarchoan[SUP] 1 [/SUP]
Affiliations
Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (M[SUP]pro[/SUP] or 3CL[SUP]pro[/SUP]) for replication and assembly. Our previous research on M[SUP]pro[/SUP] of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of M[SUP]pro[/SUP] inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits M[SUP]pro[/SUP] activity in vitro as well as in a cell-based M[SUP]pro[/SUP] 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[SUP]pro[/SUP], confirming a role for Cys300 in inhibition of WT M[SUP]pro[/SUP] 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 IC[SUB]50[/SUB]s. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 infection.
. 2024 Sep 27.
doi: 10.1039/d4md00454j. Online ahead of print. Discovery of a nasal spray steroid, tixocortol, as an inhibitor of SARS-CoV-2 main protease and viral replication
David A Davis[SUP] 1 [/SUP], Ashwin Nair[SUP] 1 [/SUP], Yana Astter[SUP] 1 [/SUP], Emma Treco[SUP] 1 [/SUP], Brian Peyser[SUP] 2 [/SUP], Rick Gussio[SUP] 3 4 [/SUP], Tam Nguyen[SUP] 2 [/SUP], Brett Eaton[SUP] 5 [/SUP], Elena Postnikova[SUP] 5 [/SUP], Michael Murphy[SUP] 5 [/SUP], Prabha Shrestha[SUP] 1 [/SUP], Haydar Bulut[SUP] 1 [/SUP], Shin-Ichiro Hattorri[SUP] 6 [/SUP], Hiroaki Mitsuya[SUP] 1 6 [/SUP], Robert Yarchoan[SUP] 1 [/SUP]
Affiliations
- PMID: 39371432
- PMCID: PMC11450544
- DOI: 10.1039/d4md00454j
Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (M[SUP]pro[/SUP] or 3CL[SUP]pro[/SUP]) for replication and assembly. Our previous research on M[SUP]pro[/SUP] of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of M[SUP]pro[/SUP] inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits M[SUP]pro[/SUP] activity in vitro as well as in a cell-based M[SUP]pro[/SUP] 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[SUP]pro[/SUP], confirming a role for Cys300 in inhibition of WT M[SUP]pro[/SUP] 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 IC[SUB]50[/SUB]s. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 infection.