Design, synthesis and biological evaluation of peptidyl keto vinyl sulfones as cysteine proteases inhibitors. Effect of the peptide structure on the activity

A family of fifteen peptidyl keto vinyl sulfones have been prepared and assayed against the cysteine proteases human cathepsin L, parasitic rhodesain and M pro from SARS-CoV-2 virus. The key synthetic step for the preparation of the keto vinyl sulfone moiety of the inhibitors was achieved through a Nozaki-Hiyama-Kishi (NHK) reaction between amino aldehydes and ( E )-β-iodo(vinyl)sulfones. Inhibitors differ on the peptide sequence and/or the substituent of the sulfone moiety. Although the inhibitors with a hydrophobic residue at P1 site were initially prepared to inhibit rhodesain and cathepsin L both belonging to papain family, and the ones with a glutamine surrogate at P1 site were made for SARS-CoV-2 M pro , unexpected results were obtained. Interestingly, the most active inhibitors against M pro were the ones with Leu at P1 site. Molecular modelling studies suggest the vinyl sulfone moiety to occupy the S1’ or S1 site of M pro acting as a glutamine surrogate. Interestingly, hit compounds are potent dual inhibitors with nanomolar activity against SARS-CoV-2 M pro (K i * = 75.2–2670 nM) and subnanomolar activity (K i * = 0.46–678 nM) against human cathepsin L. • A Nozaki-Hiyama-Kishi reac on between amino aldehydes and ( E )-b iodo(vinyl)sulfones has been applied to synthesize protease inhibitors. • Unexpectedly, inhibitors with a hydrophobic residue at P1 site were highly ac ve against SARS-CoV-2 Mpro. • Molecular modelling suggests the vinyl sulfone moiety to occupy the S1’ or S1 site of Mpro ac ng as a glutamine surrogate. • Hit compounds are potent dual inhibitors with nanomolar ac vity against SARS CoV-2 Mpro and subnanomolar ac vity against human cathepsin L.