Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 Mpro and Cathepsin

  • J Med Chem. 2025 Jun 12;68(11):10953-10969. doi: 10.1021/acs.jmedchem.4c03147.
Miriam R B Porzberg  1 ,  G J Mirjam Groenewold  2 ,  Heyrhyoung Lyoo  3 ,  Alexander K M H Jakob  1 ,  Willem H C Titulaer  1 ,  Lorenzo Cavina  1 ,  Katrien C K Poelaert  3 ,  Marleen Zwaagstra  3 ,  Cindy E J Dieteren  4 ,  Jaap G H Lemmers  4 ,  S Hakim Hamdani  4 ,  Bernd N M van Buuren  4 ,  Bart Ackerschott  4 ,  Johannes Platteeuw  5 ,  Joey Michorius  5 ,  Byron E E Martina  6 ,  Martin C Feiters  1 ,  Daniel Gironés  1  4 ,  Frank J M van Kuppeveld  3 ,  Martijn J van Hemert  2 ,  Floris P J T Rutjes  1
Affiliations
  • 1. Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands.
  • 2. Molecular Virology Laboratory, Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, Leiden 2333ZA, The Netherlands.
  • 3. Virology Section, Division of Infectious Diseases & Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, Utrecht 3584 CL, The Netherlands.
  • 4. Protinhi Therapeutics, Transistorweg 5, Nijmegen 6534 AT, The Netherlands.
  • 5. Avivia BV, Transistorweg 5, Nijmegen 6534 AT, The Netherlands.
  • 6. Artemis Bioservices, Molengraaffsingel 10, Delft 2629 JD, The Netherlands.
PMID: 40415551 DOI: 10.1021/acs.jmedchem.4c03147
Abstract

Five years after the onset of the COVID-19 pandemic, there still is an unmet need for novel antivirals to battle SARS-CoV-2 and Other coronaviruses. For this purpose, the development of peptidomimetics against the SARS-CoV-2 main protease (Mpro) and host proteases human Cathepsin L (hCTSL) and Cathepsin B (hCTSB) is an attractive strategy. These dual-mode antivirals target both viral entry and replication, which could be a suitable alternative to highly specific Mpro and CTS inhibitors. Herein, we examined the inhibitory activity, physicochemical and ADME properties, metabolic stability, and in vivo PK parameters of peptidomimetic inhibitors bearing a potent phenoxymethyl ketone warhead. Our compounds showed nanomolar inhibition of both Mpro and hCTSL/hCTSB and efficiently inhibited SARS-CoV-2 replication in Cell Culture. Furthermore, we studied metabolism and the impact of coadministration with the CYP-inhibitor ritonavir. Taken together, we report 1 as broad-spectrum coronavirus inhibitor with attractive properties to be pursued in in vivo efficacy studies.

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