2. Academic Validation
  3. Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease

Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease

  • J Med Chem. 2025 Feb 13;68(3):2920-2941. doi: 10.1021/acs.jmedchem.4c02172.
Ravi Kumar Akula 1 2,  Haifa El Kilani 2,  Alina Metzen 1 3,  Judith Röske 2,  Kaixuan Zhang 2,  Matthias Göhl 1,  Nanaji Arisetti 1,  Graham P Marsh 4,  Hannah J Maple 4,  Mark S Cooper 4,  Burhan Karadogan 4,  Dirk Jochmans 5,  Johan Neyts 5,  Katharina Rox 1 3,  Rolf Hilgenfeld 2 6,  Mark Brönstrup 1 3 7
Affiliations

Affiliations

  • 1 Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig 38124, Germany.
  • 2 Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, Lübeck 23562, Germany.
  • 3 German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Braunschweig 38124, Germany.
  • 4 Bio-Techne (Tocris), Bristol BS11 9QD, U.K.
  • 5 Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven 3000, Belgium.
  • 6 German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, Lübeck 23562, Germany.
  • 7 Institute of Organic Chemistry and Biomolecular Drug Research Centre (BMWZ), Leibniz University Hannover, Schneiderberg 1B, Hannover 30167, Germany.
PMID: 39817813 DOI: 10.1021/acs.jmedchem.4c02172
Abstract

The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported Mpro inhibitors was the peptidomimetic α-ketoamide 13b, whose cocrystal structure with Mpro paved the way for multiple lead-finding studies. We established structure-activity relationships for the 13b series by modifying residues at the P1', P3, and P4 sites. Guided by cocrystal structures, we reduced the P1' substituent size to better fill the pocket and added a fluorine substituent to the pyridone ring, enabling a new hydrogen bond with Gln189 in P3. Among 22 novel analogues, 6d and 12d inhibited Mpro with IC50s of 110 nM and 40 nM, improving the potency of 13b by up to 9.5-fold. Compound 6d had pronounced Antiviral activity with an EC50 of 1.6 μM and was stable in plasma and microsomes. The study illustrates the potential of structure-based design to systematically improve peptidomimetic α-ketoamides.

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