Discovery of a nasal spray steroid, tixocortol, as an inhibitor of SARS-CoV-2 main protease and viral replication.

Discovery of a nasal spray steroid, tixocortol, as an inhibitor of SARS-CoV-2 main protease and viral replication.

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

Original Article

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