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Medrano, Francisco J.; de la Hoz-Rodríguez, Sergio; Martí, Sergio; Arafet, Kemel; Schirmeister, Tanja; Hammerschmidt, Stefan J.; Müller, Christin; González-Martínez, Águeda; Santillana, Elena; Ziebuhr, John; Romero, Antonio; Zimmer, Collin; Weldert, Annabelle; Zimmermann, Robert; Lodola, Alessio; Świderek, Katarzyna; Moliner, Vicent; González, Florenci V.

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

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  • Medientyp: E-Artikel
  • Titel: Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2
  • Beteiligte: Medrano, Francisco J.; de la Hoz-Rodríguez, Sergio; Martí, Sergio; Arafet, Kemel; Schirmeister, Tanja; Hammerschmidt, Stefan J.; Müller, Christin; González-Martínez, Águeda; Santillana, Elena; Ziebuhr, John; Romero, Antonio; Zimmer, Collin; Weldert, Annabelle; Zimmermann, Robert; Lodola, Alessio; Świderek, Katarzyna; Moliner, Vicent; González, Florenci V.
  • Erschienen: Springer Science and Business Media LLC, 2024
  • Erschienen in: Communications Chemistry
  • Sprache: Englisch
  • DOI: 10.1038/s42004-024-01104-7
  • ISSN: 2399-3669
  • Schlagwörter: Materials Chemistry ; Biochemistry ; Environmental Chemistry ; General Chemistry
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main protease (M<jats:sup>pro</jats:sup>) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting enzyme inhibitory activity against M<jats:sup>pro</jats:sup> (<jats:italic>K</jats:italic><jats:sub><jats:italic>i</jats:italic></jats:sub>: 1–10 μM) good anti-SARS-CoV-2 infection activity in the low micromolar range (EC<jats:sub>50</jats:sub>: 1–12 μM) without significant toxicity. Additional kinetic studies of compounds <jats:bold>FGA145</jats:bold>, <jats:bold>FGA146</jats:bold> and <jats:bold>FGA147</jats:bold> 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 <jats:bold>FGA146</jats:bold> and <jats:bold>FGA147</jats:bold> to the active site of the protein. Furthermore, our results illustrate that peptidyl nitroalkenes are effective covalent reversible inhibitors of the M<jats:sup>pro</jats:sup> and cathepsin L, and that inhibitors <jats:bold>FGA145</jats:bold>, <jats:bold>FGA146</jats:bold> and <jats:bold>FGA147</jats:bold> prevent infection against SARS-CoV-2.</jats:p>
  • Zugangsstatus: Freier Zugang