Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2
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Other documents of the author: Medrano Martin, Francisco Javier; De la Hoz Rodríguez, Sergio; Martí, Sergio; Arafet Cruz, Kemel; Schirmeister, Tanja; Hammerschmidt, Stefan Josef; Müller-Ruttloff, Christin; González-Martínez, Águeda; Santillana Heras, Elena; Ziebuhr, John; Romero Garrido, Antonio; Zimmer, Collin; Weldert, Annabelle Carolin; Zimmermann, Robert; Lodola, Alessio; Świderek, Katarzyna; Moliner, Vicent; González, Florenci
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Title
Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2Author (s)
Date
2024-01-18Publisher
Springer NatureBibliographic citation
Medrano, F.J., de la Hoz-Rodríguez, S., Martí, S. et al. Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2. Commun Chem 7, 15 (2024). https://doi.org/10.1038/s42004-024-01104-7Type
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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 ... [+]
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. [-]
Funder Name
Consejo Superior de Investigaciones Científicas (CSIC) | Ministerio de Ciencia, Innovación y Universidades, Spain | Generalitat Valenciana | Fondo Social Europeo | University Medical Center Giessen and Marburg | von Behring-Röntgen-Stiftung | Deutsche Forschungsgemeinschaſt | Barcelona Supercomputing Center | European Regional Development Fund
Project code
PIE-202020E224 | PID2021-123332OB-C21 | PID2019-107098RJ-I00 | CIPROM/2021/079 | SEJI/2020/007 | UJI-B2020-03 | UJI-B2021-71 | RYC2020-030596-I | 71_0016 | 530813989 | QH-2022-2-0004 | QH-2022-3-0008 | IDIFEDER/2021/02
Project title or grant
SomUJIcontracovid crowdfunding campaign
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© The Author(s) 2024
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info:eu-repo/semantics/openAccess
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