Author: Brönstrup, Mark ; Sauerhering, Lucie ; Zhang, Linlin ; Hilgenfeld, Rolf ; Cowell, Justin K. ; Becker, Stephan ; Neyts, Johan ; Cooper, Mark S. ; Ibrahim, Mohamed ; Zhang, Kaixuan ; Sun, Xinyuanyuan ; Göhl, Matthias ; Röske, Judith ; Jochmans, Dirk ; Maple, Hannah J. ; Vangeel, Laura ; Rox, Katharina ; Marsh, Graham P.

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (M^pro, 3CL^pro) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. M^pro is therefore an attractive target for the design of inhibitors that block viral replication. We report the diastereomeric resolution of the previously designed SARS-CoV-2 M^pro α-ketoamide inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC₅₀ of 120 nM against the M^pro and EC₅₀ values of 0.8-3.4 μM for antiviral activity in different cell types. Crystal structures have been elucidated for the M^pro complexes with each of the major diastereomers, the active (S,S,S)-13b (13b-K), and the nearly inactive (R,S,S)-13b (13b-H); results for the latter reveal a novel binding mode. Pharmacokinetic studies show good levels of 13b-K after inhalative as well as after peroral administration. The active inhibitor (13b-K) is a promising candidate for further development as an antiviral treatment for COVID-19.

03 Jun 2022·Expert Opinion on Drug DiscoveryQ3 · MEDICINE

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?

Q3 · MEDICINE

Article

Author: Capasso, Clemente ; Supuran, Claudiu T. ; Nocentini, Alessio

INTRODUCTIONThe 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).AREAS COVEREDThe 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).EXPERT OPINIONCrystallography, 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.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	DE	Universität zu Lübeck	-
COVID-19	Preclinical	GB	Tocris Bioscience	-

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