A non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication biorxivpreprint utmbhealth SARSCoV2 COVID19 coronavirus covid protease inhibitor enzyme replication
By Bhavana KunkalikarAug 16 2022Reviewed by Danielle Ellis, B.Sc. In a recent study posted to the bioRxiv* preprint server, researchers assessed highly potent non-covalent inhibitors of severe acute respiratory syndrome coronavirus 2 3-chymotrypsin-like protease .
The team screened deoxyribonucleic acid encoded libraries of over 49 million compounds with hexahistidine -tagged purified recombinant SARS-CoV-2 3CLpro, which was bound to nickel -nitrilotriacetic acid magnetic beads. Additionally, His6-tag was engineered into 3CLpro without impacting the protease activity. Furthermore, the 3CLpro-mHis was immobilized on the magnetic beads and incubated with DEL.
Results The study results showed that SARS-CoV-2 3CLpro crystal structures displayed Thr225 and Gly215 in the loop located at the far end of the dimer interface and catalytic site. A fluorescence-based assay revealed that the protease activity of the His6-tagged 3CLpro, called 3CLpro-mHis, was compared to that observed in the wild-type 3CLpro. Four of the potential 3CLpro binders inhibited 3CLpro with a half-maximal inhibitory concentration of less than 1µM.
Other reported structures had either a γ-lactam, a cyclobutyl, a pyridine, a benzotriazole, or a 1-methyl-1H-1,2,4- triazole moiety that docked into the 3CLpro S1 site. The team noted that the key distinction between the reported inhibitors and WU-04 was the presence of a bromophenyl ring in WU-04 that docked well into the S2 and S4 sites.
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