48. Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors

Jelisejevs D., Bula A. L., Kinena L. Bioorg. Med. Chem. Lett. 2023, 96, 129530
DOI: 10.1016/j.bmcl.2023.129530.

Abstract

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.