Peptidyl Nitroalkene Inhibitors of Main Protease Rationalized by Computational and Crystallographic Investigations As Antivirals Against SARS-CoV-2

Overview

Journal Commun Chem

Publisher Springer Nature

Specialty Chemistry

Date 2024 Jan 18

PMID 38238420

Authors

Francisco J Medrano

Sergio de la Hoz-Rodriguez

Sergio Marti

Kemel Arafet

Tanja Schirmeister

Stefan J Hammerschmidt

Christin Muller

Agueda Gonzalez-Martinez

Elena Santillana

John Ziebuhr

Antonio Romero

Collin Zimmer

Annabelle Weldert

Robert Zimmermann

Alessio Lodola

Katarzyna Swiderek

Vicent Moliner

Florenci V Gonzalez

Affiliations

Soon will be listed here.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main protease (M) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting enzyme inhibitory activity against M (K: 1-10 μM) good anti-SARS-CoV-2 infection activity in the low micromolar range (EC: 1-12 μM) without significant toxicity. Additional kinetic studies of compounds FGA145, FGA146 and FGA147 show that all three compounds inhibit cathepsin L, denoting a possible multitarget effect of these compounds in the antiviral activity. Structural analysis shows the binding mode of FGA146 and FGA147 to the active site of the protein. Furthermore, our results illustrate that peptidyl nitroalkenes are effective covalent reversible inhibitors of the M and cathepsin L, and that inhibitors FGA145, FGA146 and FGA147 prevent infection against SARS-CoV-2.

Citing Articles

Exploring covalent inhibitors of SARS-CoV-2 main protease: from peptidomimetics to novel scaffolds.

Atatreh N, Mahgoub R, Ghattas M J Enzyme Inhib Med Chem. 2025; 40(1):2460045.

PMID: 39912405 PMC: 11803818. DOI: 10.1080/14756366.2025.2460045.

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