2. Academic Validation
  3. Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease

  • J Med Chem. 2022 Oct 13;65(19):13328-13342. doi: 10.1021/acs.jmedchem.2c01131.
Mark S Cooper 1,  Linlin Zhang 2,  Mohamed Ibrahim 2,  Kaixuan Zhang 2,  Xinyuanyuan Sun 2,  Judith Röske 2,  Matthias Göhl 3,  Mark Brönstrup 3 4,  Justin K Cowell 1,  Lucie Sauerhering 5,  Stephan Becker 5 6,  Laura Vangeel 7,  Dirk Jochmans 7,  Johan Neyts 7,  Katharina Rox 3 4,  Graham P Marsh 1,  Hannah J Maple 1,  Rolf Hilgenfeld 2 8
Affiliations

Affiliations

  • 1 Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Bristol, BS11 9QD, U.K.
  • 2 Institute of Molecular Medicine, University of Lübeck, 23562 Lübeck, Germany.
  • 3 Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
  • 4 German Center for Infection Research (DZIF), Partner Site Braunschweig-Hannover, 38124 Braunschweig, Germany.
  • 5 Institute of Virology, University of Marburg, 35043 Marburg, Germany.
  • 6 German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, 35043 Marburg, Germany.
  • 7 Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, B-3000 Leuven, Belgium.
  • 8 German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.
PMID: 36179320 DOI: 10.1021/acs.jmedchem.2c01131
Abstract

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main Protease (Mpro, 3CLpro) of SARS-CoV-2 is a key Enzyme that processes polyproteins translated from the viral RNA. Mpro 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 Mpro α-ketoamide inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC50 of 120 nM against the Mpro and EC50 values of 0.8-3.4 μM for Antiviral activity in different cell types. Crystal structures have been elucidated for the Mpro 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.

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