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

Research output: Contribution to journal › Article › Research › peer review

Authors

  • Ravi Kumar Akula
  • Haifa El Kilani
  • Alina Metzen
  • Judith Röske
  • Mark Brönstrup

Research Organisations

External Research Organisations

  • Helmholtz Centre for Infection Research (HZI)
  • Universität zu Lübeck
  • German Center for Infection Research (DZIF)
  • Bio-Techne Corporation
  • KU Leuven
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Details

Original languageEnglish
Pages (from-to)2920–2941
Number of pages22
JournalJournal of medicinal chemistry
Volume68
Issue number3
Early online date16 Jan 2025
Publication statusPublished - 13 Feb 2025

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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Cite this

Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease. / Akula, Ravi Kumar; El Kilani, Haifa; Metzen, Alina et al.
In: Journal of medicinal chemistry, Vol. 68, No. 3, 13.02.2025, p. 2920–2941.

Research output: Contribution to journal › Article › Research › peer review

Akula, RK, El Kilani, H, Metzen, A, Röske, J, Zhang, K, Göhl, M, Arisetti, N, Marsh, GP, Maple, HJ, Cooper, MS, Karadogan, B, Jochmans, D, Neyts, J, Rox, K, Hilgenfeld, R & Brönstrup, M 2025, 'Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease', Journal of medicinal chemistry, vol. 68, no. 3, pp. 2920–2941. https://doi.org/10.1021/acs.jmedchem.4c02172
Akula, R. K., El Kilani, H., Metzen, A., Röske, J., Zhang, K., Göhl, M., Arisetti, N., Marsh, G. P., Maple, H. J., Cooper, M. S., Karadogan, B., Jochmans, D., Neyts, J., Rox, K., Hilgenfeld, R., & Brönstrup, M. (2025). Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease. Journal of medicinal chemistry, 68(3), 2920–2941. https://doi.org/10.1021/acs.jmedchem.4c02172
Akula RK, El Kilani H, Metzen A, Röske J, Zhang K, Göhl M et al. Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease. Journal of medicinal chemistry. 2025 Feb 13;68(3):2920–2941. Epub 2025 Jan 16. doi: 10.1021/acs.jmedchem.4c02172
Akula, Ravi Kumar ; El Kilani, Haifa ; Metzen, Alina et al. / Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease. In: Journal of medicinal chemistry. 2025 ; Vol. 68, No. 3. pp. 2920–2941.
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AU - Akula, Ravi Kumar

AU - El Kilani, Haifa

AU - Metzen, Alina

AU - Röske, Judith

AU - Zhang, Kaixuan

AU - Göhl, Matthias

AU - Arisetti, Nanaji

AU - Marsh, Graham P.

AU - Maple, Hannah J.

AU - Cooper, Mark S.

AU - Karadogan, Burhan

AU - Jochmans, Dirk

AU - Neyts, Johan

AU - Rox, Katharina

AU - Hilgenfeld, Rolf

AU - Brönstrup, Mark

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PY - 2025/2/13

Y1 - 2025/2/13

N2 - 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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