Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease
The main protease M<sup>pro</sup> is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M<sup>pro</sup> inhibitors was the peptidomimetic α-ketoamide <b>13b</b>, whose cocrystal structure with M<sup>pro</sup> paved the way for multiple lead-finding studies. We established structure-activity relationships for the <b>13b</b> 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, <b>6d</b> and <b>12d</b> inhibited M<sup>pro</sup> with IC<sub>50</sub>s of 110 nM and 40 nM, improving the potency of <b>13b</b> by up to 9.5-fold. Compound <b>6d</b> had pronounced antiviral activity with an EC<sub>50</sub> 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.
Authors
- Nanaji Arisetti
- Burhan Karadogan
- Matthias Göhl
- Mark S. Cooper (ORCID: https://orcid.org/0000-0003-3112-7728)
- Mark Brönstrup (ORCID: https://orcid.org/0000-0002-8971-7045)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Rolf Hilgenfeld (ORCID: https://orcid.org/0000-0001-8850-2977)
- Haifa El Kilani (ORCID: https://orcid.org/0000-0003-4084-3582)
- Hannah J. Maple (ORCID: https://orcid.org/0000-0001-5050-0562)
- Graham P. Marsh (ORCID: https://orcid.org/0000-0003-0375-5145)
- Judith Röske (ORCID: https://orcid.org/0009-0001-7776-9729)
- Dirk Jochmans (ORCID: https://orcid.org/0000-0002-9265-6028)
- Johan Neyts (ORCID: https://orcid.org/0000-0002-0033-7514)
- A. Ravi Kumar (ORCID: https://orcid.org/0000-0003-3217-7989)
- Kaixuan Zhang (ORCID: https://orcid.org/0009-0001-5894-6507)
- Alina Metzen
Institutions
- Leibniz University Hannover (DE)
- Rega Institute for Medical Research (BE)
- At Bristol (GB)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- R&D Systems (United States) (US)
- University of Lübeck (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02172
- Citations
- 4
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 6.02
Funders
- Deutsches Zentrum für Infektionsforschung
- Universität zu Lübeck
- Niedersächsisches Ministerium für Wissenschaft und Kultur
- Deutsches Elektronen-Synchrotron