Peptidyl Acyloxymethyl Ketones as Activity-Based Probes for the Main Protease of SARS-CoV-2

Abstract

<div>The global pandemic caused by SARS-CoV-2 calls for a fast development of antiviral drugs </div><div>against this particular coronavirus. Chemical tools to facilitate inhibitor discovery as well as </div><div>detection of target engagement by hit or lead compounds from high throughput screens are </div><div>therefore in urgent need. We here report novel, selective activity-based probes that enable </div><div>detection of the SARS-CoV-2 main protease. The probes are based on acyloxymethyl ketone </div><div>reactive electrophiles combined with a peptide sequence including non-natural amino acids </div><div>that targets the non-primed site of the main protease substrate binding cleft. They are the first </div><div>activity-based probes for the main protease of coronaviruses and display target labeling within </div><div>in a human proteome without background. We expect that these reagents will be useful in the </div><div>drug development pipeline, not only for the current SARS-CoV-2, but also for other </div><div>coronaviruses. </div>