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?

Introduction: The main cysteine protease from SARS-CoV-2 (Mpro), 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 (paxlovidTM). Areas covered: The authors review the scientific literature on the drug design landscape of α-ketoamide SARS-CoV-2 Mpro 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). Expert opinion: 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 Mpro 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.