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. 2023 Nov 15:96:129530.
doi: 10.1016/j.bmcl.2023.129530. Epub 2023 Oct 20.

Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors

Daniels Jelisejevs  1 , Anna Lina Bula  1 , Linda Kinena  2
Affiliations

Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors

Daniels Jelisejevs et al. Bioorg Med Chem Lett. .

Abstract

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 β- and γ-lactams as electrophilic "warheads" for covalent binding to Cys145 of the Mpro 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 Mpro.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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