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

Davis et al., RSC Medicinal Chemistry, doi:10.1039/d4md00454j
Sep 2024  
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In Silico and In Vitro study showing that tixocortol pivalate inhibits SARS-CoV-2 main protease (Mpro) activity and viral replication. The steroid tixocortol was identified through molecular docking as potentially binding to Mpro at the Cys300 pocket. In Vitro, tixocortol inhibited Mpro activity, showing non-competitive inhibition with an apparent Ki of 2.5 μM. Mass spectrometry confirmed that tixocortol covalently modifies Mpro, with up to 2 tixocortol molecules binding per Mpro molecule. In HeLa-ACE2 cells, tixocortol pivalate, a prodrug of tixocortol, inhibited SARS-CoV-2 replication with IC50 values of 1.5-2.1 μM. The related steroid hydrocortisone showed no Mpro inhibition or antiviral activity.
Davis et al., 27 Sep 2024, peer-reviewed, 15 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMiscellaneousAll
DB03760 (R)-dihydrolipoic acid -1.06 95 + /-14 no Table S1 : List of compounds identified based on docking prediction at Cys300 pocket in SARS-CoV-2 M pro and their ability covalently modify M pro and affect M pro activity. Pipeline Pilot produced 72 compounds with -SH groups that could potentially dock at Cys300. To determine the feasibility of covalent binding, these thiol compounds were covalently docked into the SARS-CoV-2 M pro crystal structure. Maestro 12.7 was used to prepare the template crystal structure 7MHI. We identified 15 compounds with docking scores favorable for the Cys300 pocket and 13 of these compounds were obtained for testing. (A) Docking scores obtained using Covalent Docking module to model the covalent ligand-protein complex using the reactive residue set at Cys300. Reaction Type of Disulfide Formation, and Docking Mode set at Virtual Screening. Note that glutathione's docking score (not shown) was -4.213. (B) M pro activity was measured using a peptide based HPLC assay using 100 nM M pro and 50 µM of each drug (see supplemental slide 1). Drugs were incubated for 1-hr then the assay was started with addition of peptide substrate and stopped after 10 minutes. Products were determined by measuring their absorbance at 205. Control was 5% DMSO and all samples contained 5% DMSO in assay. Note that only tixocortol showed significant inhibitory activity against M pro while most others showed increased activity. (C) Each compound (50 µM) was incubated with M pro (5 µM) for 1 hr in assay buffer and then analyzed by SEC/MS to assess covalent modification based on the amu for M pro species.
References
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