Pyrazolidinone-based peptidomimetic SARS-CoV-2 M^pro inhibitors

The main protease (M^pro) 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 β- and γ-lactams as electrophilic "warheads" for covalent binding to Cys145 of the M^pro active site. The highest inhibitory activity (IC₅₀ = 45 ± 3 μM) 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 M^pro.