Design of SARS‑CoV‑2 Mpro Inhibitors Based on Lactam Scaffold

Linda Kinena

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Design of SARS‑CoV‑2 Mpro Inhibitors Based on Lactam Scaffold

Linda Kinena

¹ Latvian Institute of Organic Synthesis

Academic Editor: Maria Emília Sousa

Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session Small molecules as drug candidates

https://doi.org/10.3390/ECMC2022-13450 (registering DOI)

Abstract:

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted an urgent need for development of new antiviral drugs. The main protease (Mpro) of SARS-CoV-2 plays an important role in viral replication and has become as an attractive drug target for virus inhibition. The active site of SARS-CoV-2 Mpro contains Cys145 and His41 which allows to use structural subunits (or “warheads”) for covalent binding to the thiol of a cysteine residue in the active site of cysteine proteases.

In our design of inhibitors considerably less chemically reactive and non-toxic lactams and their structural analogues as “warheads” for covalent inhibition of SARS-CoV-2 proteases Mpro were chosen. β- And ɣ-lactam subunit serves as the warhead for the covalent modification of cysteine proteases with the mechanism of action involving the cleavage of β-lactam ring by cysteine residue in the active site of the enzyme.

For chosen β- and ɣ-lactams IC₅₀ values for M^pro inhibition were determined using fluorescence resonance energy transfer (FRET) assay. For inhibitory activity improvement (1H-indole-2-carbonyl)-L-phenylalanine moiety was introduced.

Acknowledgements

This work was supported by the project 1.1.1.2/VIAA/4/20/754 “Development of lactam-based inhibitors of SARS-CoV-2 Mpro and other viral proteases”.

Keywords: SARS-CoV-2 Mpro; lactams; covalent binding; cysteine protease

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otis jame

1 December 2022

The design of SARS‑CoV‑2 Mpro inhibitors based on lactam scaffold is under study. among us The lactam scaffold is a scaffold that is able to inhibit the replication of SARS‑CoV‑2 in vitro and in vivo. The study is designed to develop a scaffold that can inhibit the replication of SARS‑CoV‑2 in vitro and in vivo using a human cell line. The study is also designed to study the safety and efficacy of the scaffold.

Linda Kinena