Abstract
The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
Highlights
The main protease, Mpro in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide
We examine whether GC373 and GC376, established as effective drugs in cats, inhibit SARS-CoV-2 Mpro reversibly and have potential for use as antiviral therapy in humans
We synthesized the key dipeptidyl compounds, aldehyde GC373 and bisulphite adduct GC376 (Fig. 1a)[10] (Supplementary Figs. 1–12), to test whether these FCoV and FIPV inhibitors are efficacious toward the Mpro of the SARS-CoV-2 and Mpro from SARS-CoV, which have very similar aminoacid sequences: 95% identity/98% similarity
Summary
The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. We developed peptide-based inhibitors, including aldehydes, against viral cysteine proteases[7] that were subsequently studied with Mpro during the SARS coronavirus (SARS-CoV) outbreak in 20039. Peptide aldehydes and their bisulphite derivatives were later used to inhibit the main protease of the Feline Coronavirus FCoV10. Structures of the SARS-CoV-2 Mpro protease were solved with a peptide-based ketoamide inhibitor[15] and various re-purposed drugs such as anticancer agents[16] These Mpro inhibitors have not been tested in animal models of coronavirus infection nor have they been reported in human or animal trials for SARS. We examine whether GC373 and GC376, established as effective drugs in cats, inhibit SARS-CoV-2 Mpro reversibly and have potential for use as antiviral therapy in humans
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