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

authored by: Ravi Kumar Akula, Haifa El Kilani, Alina Metzen, Judith Röske, Kaixuan Zhang, Matthias Göhl, Nanaji Arisetti, Graham P. Marsh, Hannah J. Maple, Mark S. Cooper, Burhan Karadogan, Dirk Jochmans, Johan Neyts, Katharina Rox, Rolf Hilgenfeld, Mark Brönstrup
Abstract: The main protease M^pro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M^pro inhibitors was the peptidomimetic α-ketoamide 13b, whose cocrystal structure with M^pro 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 M^pro 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.
Organisation(s): Centre of Biomolecular Drug Research (BMWZ)
Institute of Organic Chemistry
External Organisation(s): Helmholtz Centre for Infection Research (HZI)
Universität zu Lübeck
German Center for Infection Research (DZIF)
Bio-Techne Corporation
KU Leuven
Type: Article
Journal: Journal of medicinal chemistry
No. of pages: 22
ISSN: 0022-2623
Publication date: 16.01.2025
Publication status: E-pub ahead of print
Peer reviewed: Yes
ASJC Scopus subject areas: Molecular Medicine, Drug Discovery
Electronic version(s): https://doi.org/10.1021/acs.jmedchem.4c02172 (Access: Open)

BibTeX

@article{0378a34fdf294a1d850ad4cd77049ea7,
title = "Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease",
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.",
author = "Akula, {Ravi Kumar} and {El Kilani}, Haifa and Alina Metzen and Judith R{\"o}ske and Kaixuan Zhang and Matthias G{\"o}hl and Nanaji Arisetti and Marsh, {Graham P.} and Maple, {Hannah J.} and Cooper, {Mark S.} and Burhan Karadogan and Dirk Jochmans and Johan Neyts and Katharina Rox and Rolf Hilgenfeld and Mark Br{\"o}nstrup",
note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society.",
year = "2025",
month = jan,
day = "16",
doi = "10.1021/acs.jmedchem.4c02172",
language = "English",
journal = "Journal of medicinal chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
}