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The main cysteine protease from SARS-CoV-2 (M pro ), conserved among many pathogenic coronaviruses, represents a recently validated antiviral drug target, with at least one inhibitor recently approved for clinical use as an antiviral drug, nirmatrelvir (paxlovid TM ). The authors review the scientific literature on the drug design landscape of α-ketoamide SARS-CoV-2 M pro  inhibitors. The X-ray/neutron crystal structure of three such compounds is available, which has allowed for drug design rationalization. The α-ketoamide functionality of the inhibitors reacts with the catalytic dyad cysteine residue to form a hemithioketal. The S3, S2, and S1’ subsites of the protease are filled with various aromatic or aliphatic (cyclic/acyclic) moieties of the peptidomimetic, whereas in S1, the preferred moiety was a rigid 2-pyrrolidone or norvaline side chain (as in telaprevir). Crystallography, previous drug design efforts, and many computational studies have allowed for a deeper understanding of the structural requirements needed for designing effective SARS-CoV-2 M pro  α-ketoamide inhibitors. However, all the reported derivatives are peptidomimetics with a rather high molecular weight. It is expected that effective compounds with lower molecular weights and a lesser peptidomimetic profile will be the target for future drug development.

Perspectives on the design and discovery of α-ketoamide inhibitors for the treatment of novel coronavirus: where do we stand and where do we go?