Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 M pro and Cathepsin
Miriam R. B. Porzberg, G. J. Mirjam Groenewold, Heyrhyoung Lyoo, Alexander K.M.H. Jakob, Willem H. C. Titulaer, Lorenzo Cavina, Katrien C. K. Poelaert, Marleen Zwaagstra, Cindy E. J. Dieteren, Jaap G. H. Lemmers, Said Hakim Hamdani, Bernd N. M. van Buuren, Bart Ackerschott, Johannes Platteeuw, Joey Michorius, B. E. E. Martina, Martin C. Feiters, Daniel Gironés, Frank J. M. van Kuppeveld, Martijn J. van Hemert · Journal of Medicinal Chemistry · 2025
High Resolution Image Download MS PowerPoint Slide 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 pro ) 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 pro 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 pro 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.