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

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

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.

Figures
Products