Peptidomimetic phenoxymethyl ketone warheads as potent dual-mode inhibitors against SARS-CoV-2 Mpro and cathepsin

Author(s):
Porzberg, M.R.B.; Groenewold, G.J.M.; Lyoo, H.; Jakob, A.K.M.H.; Titulaer, W.H.C.; Cavina, L.; Poelaert, K.C.K.; Zwaagstra, M.; Dieteren, C.E.J.; Lemmers, J.G.H.; Hamdani, S.H.; Buuren, B.N.M. van; Ackerschott, B.; Platteeuw, J.; Michorius, J.; Martina, B.E.E.; Feiters, M.C.; Gironés, D.; Kuppeveld, F.J.M. van; Hemert, M.J. van (0000-0002-2617-9243); Rutjes, F.P.J.T.
Published
2025
Publication type
Article / Letter to editor

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.

Date issued
2025-05-26
Language
English
Publisher
American Chemical Society
Is part of
Journal of Medicinal Chemistry (2025), Vol. 68, no. 11, p. 10953-10969
hdl
1887/4282411
doi
10.1021/acs.jmedchem.4c03147
URL
https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03147