Journal of medicinal chemistry · 2025
Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 Mpro and Cathepsin.
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Porzberg Miriam R B, Groenewold G J Mirjam, Lyoo Heyrhyoung, Jakob Alexander K M H, Titulaer Willem H C, Cavina Lorenzo, Poelaert Katrien C K, Zwaagstra Marleen, Dieteren Cindy E J, Lemmers Jaap G H, Hamdani S Hakim, van Buuren Bernd N M, Ackerschott Bart, Platteeuw Johannes, Michorius Joey, Martina Byron E E, Feiters Martin C, Gironés Daniel, van Kuppeveld Frank J M, van Hemert Martijn J, Rutjes Floris P J T
Аннотация
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.