2. Academic Validation
  3. 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

  • RSC Med Chem. 2024 Sep 27;15(12):4193-4205. doi: 10.1039/d4md00454j.
David A Davis 1,  Ashwin Nair 1,  Yana Astter 1,  Emma Treco 1,  Brian Peyser 2,  Rick Gussio 3 4,  Tam Nguyen 2,  Brett Eaton 5,  Elena Postnikova 5,  Michael Murphy 5,  Prabha Shrestha 1,  Haydar Bulut 1,  Shin-Ichiro Hattorri 6,  Hiroaki Mitsuya 1 6,  Robert Yarchoan 1
Affiliations

Affiliations

  • 1 HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute Bethesda MD USA david.davis@nih.gov.
  • 2 Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health USA.
  • 3 Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research Frederick MD 21702 USA.
  • 4 Computational Institute for Health and Environmental Research, (CIFHER.ORG) Riverside 5, RM 4076, 8490 Progress Dr. Frederick MD 21701 USA.
  • 5 Integrated Research Facility at Fort Detrick 8200 Research Plaza Frederick MD 21702 USA.
  • 6 Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute 1-21-1 Toyama Shinjuku-ku Tokyo 162-8655 Japan.
PMID: 39371432 DOI: 10.1039/d4md00454j
Abstract

Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (Mpro or 3CLpro) for replication and assembly. Our previous research on Mpro of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of Mpro inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits Mpro activity in vitro as well as in a cell-based Mpro 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 Mpro, confirming a role for Cys300 in inhibition of WT Mpro 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 IC50s. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 Infection.

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