Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 M<sup>pro</sup> and Cathepsin
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 (M<sup>pro</sup>) 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 M<sup>pro</sup> 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 M<sup>pro</sup> 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 <b>1</b> as broad-spectrum coronavirus inhibitor with attractive properties to be pursued in <i>in vivo</i> efficacy studies.
Authors
- Alexander K.M.H. Jakob
- Katrien C. K. Poelaert
- Miriam R. B. Porzberg (ORCID: https://orcid.org/0000-0002-1163-3722)
- Daniel Gironés
- Willem Titulaer
- Frank J. M. van Kuppeveld (ORCID: https://orcid.org/0000-0001-5800-749X)
- Cindy E. Dieteren
- Heyrhyoung Lyoo (ORCID: https://orcid.org/0000-0001-5806-9463)
- G. J. Mirjam Groenewold (ORCID: https://orcid.org/0000-0001-6280-7297)
- Bernd N. M. van Buuren (ORCID: https://orcid.org/0000-0003-2021-1123)
- Floris P. J. T. Rutjes (ORCID: https://orcid.org/0000-0003-1538-3852)
- Jaap G. H. Lemmers
- B Martina (ORCID: https://orcid.org/0000-0003-4980-4619)
- Martin C. Feiters (ORCID: https://orcid.org/0000-0003-0130-835X)
- Marleen Zwaagstra (ORCID: https://orcid.org/0000-0002-6774-1503)
- Martijn J. van Hemert (ORCID: https://orcid.org/0000-0002-2617-9243)
- Lorenzo Cavina (ORCID: https://orcid.org/0000-0001-6700-1559)
- Said Hakim Hamdani
- Bart Ackerschott
- Johannes Platteeuw
- Joey Michorius
Institutions
- Radboud University Nijmegen (NL)
- Utrecht University (NL)
- Leiden University Medical Center (NL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03147
- Citations
- 1
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 1.50
Funders
- Health~Holland
- Universiteit Leiden
- ZonMw
- Universiteit Utrecht
- Radboud Universiteit
- Leids Universitair Medisch Centrum