Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 M 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) 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 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 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 as broad-spectrum coronavirus inhibitor with attractive properties to be pursued in efficacy studies.