2. Academic Validation
  3. Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2

Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2

  • Commun Chem. 2024 Jan 18;7(1):15. doi: 10.1038/s42004-024-01104-7.
Francisco J Medrano 1,  Sergio de la Hoz-Rodríguez 2,  Sergio Martí 3,  Kemel Arafet 3,  Tanja Schirmeister 4,  Stefan J Hammerschmidt 4,  Christin Müller 5,  Águeda González-Martínez 6,  Elena Santillana 6,  John Ziebuhr 5,  Antonio Romero 6,  Collin Zimmer 4,  Annabelle Weldert 4,  Robert Zimmermann 4,  Alessio Lodola 7,  Katarzyna Świderek 3,  Vicent Moliner 8,  Florenci V González 9
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. fjmedrano@cib.csic.es.
  • 2 Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12071, Castelló, Spain.
  • 3 Departament de Química Física i Analítica, Universitat Jaume I, 12071, Castelló, Spain.
  • 4 Institute of Pharmaceutical and BiomedicalSciences, Johannes Gutenberg-University Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
  • 5 Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, 35392, Giessen, Germany.
  • 6 Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
  • 7 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy.
  • 8 Departament de Química Física i Analítica, Universitat Jaume I, 12071, Castelló, Spain. moliner@uji.es.
  • 9 Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12071, Castelló, Spain. fgonzale@uji.es.
PMID: 38238420 DOI: 10.1038/s42004-024-01104-7
Abstract

The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main Protease (Mpro) represents one of the most attractive targets for the development of Antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting Enzyme inhibitory activity against Mpro (Ki: 1-10 μM) good anti-SARS-CoV-2 Infection activity in the low micromolar range (EC50: 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 Mpro and Cathepsin L, and that inhibitors FGA145, FGA146 and FGA147 prevent Infection against SARS-CoV-2.

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