Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray S...

ID: ALA5131566

Journal: J Med Chem

Title: Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination.

Authors: Pillaiyar T, Flury P, Krüger N, Su H, Schäkel L, Barbosa Da Silva E, Eppler O, Kronenberger T, Nie T, Luedtke S, Rocha C, Sylvester K, Petry MRI, McKerrow JH, Poso A, Pöhlmann S, Gütschow M, O'Donoghue AJ, Xu Y, Müller CE, Laufer SA.

Abstract: The main protease (M^pro, 3CL^pro) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M^pro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 M^pro inhibition with k_inac/K_i of 58,700 M^-1 s^-1 (K_i = 0.0141 μM) and 27,200 M^-1 s^-1 (K_i = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 M^pro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M^pro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

CiteXplore: 35709506

DOI: 10.1021/acs.jmedchem.2c00636

Patent ID: ┄