Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors

The main protease (Mpro) of SARS-CoV-2 is an attractive drug target for COVID-19 treatment as it plays an integral role in the proliferation of coronavirus. Herein, we describe the investigation of /q-and y-lactams as electrophilic warheads for covalent binding to Cys145 of the Mpro active site. The highest inhibitory activity (IC50 = 45 +/- 3 mu M) was achieved using a pyrazolidinone warhead attached to the targeting dipeptide. Importantly, the synergy of the warhead and the targeting dipeptide is crucial for the successful inhibition of Mpro.

Automated summary

The study investigates /q- and y-lactams as electrophilic warheads for covalently targeting the Mpro active site at Cys145. The highest inhibitory activity was achieved using a pyrazolidinone warhead attached to the targeting dipeptide. Notably, the synergy between the warhead and the targeting dipeptide is crucial for the successful inhibition of Mpro.