Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors

Daniels Jelisejevs; Anna Lina Bula; Linda Kinena

doi:10.1016/j.bmcl.2023.129530

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

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

Authors

Daniels Jelisejevs¹, Anna Lina Bula¹, Linda Kinena²

Affiliations

¹ Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
² Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia. Electronic address: linda@osi.lv.

PMID: 37866713
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19 Drug Treatment
COVID-19*
Dipeptides
Humans
Peptidomimetics* / pharmacology
SARS-CoV-2

Substances

Peptidomimetics
Dipeptides