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

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.

2022-06-03·Expert opinion on drug discovery3区 · 医学

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?

3区 · 医学

Article

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

INTRODUCTION:

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).

AREAS COVERED:

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).

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 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.

100 项与 Mpro13b-K 相关的药物交易

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