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Commun Chem
. 2024 Jan 18;7(1):15.
doi: 10.1038/s42004-024-01104-7. Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2
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
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.
. 2024 Jan 18;7(1):15.
doi: 10.1038/s42004-024-01104-7. Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2
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
- PMID: 38238420
- DOI: 10.1038/s42004-024-01104-7
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.