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Obermann, Wiebke; Azri, Mohammad Farhan Darin; Konopka, Leonie; Schmidt, Nina; Magari, Francesca; Sherman, Julian; Silva, Liliana M. R.; Hermosilla, Carlos; Ludewig, Andreas H.; Houhou, Hicham; Haeberlein, Simone; Luo, Mona Yiting; Häcker, Irina; Schetelig, Marc F.; Grevelding, Christoph G.; Schroeder, Frank C.; Lau, Gilbert Sei Kung; Taubert, Anja; Rodriguez, Ana; Heine, Andreas; Yeo, Tiong Chia; Grünweller, Arnold; Taroncher-Oldenburg, Gaspar

Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates

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  • Medientyp: E-Artikel
  • Titel: Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates
  • Beteiligte: Obermann, Wiebke; Azri, Mohammad Farhan Darin; Konopka, Leonie; Schmidt, Nina; Magari, Francesca; Sherman, Julian; Silva, Liliana M. R.; Hermosilla, Carlos; Ludewig, Andreas H.; Houhou, Hicham; Haeberlein, Simone; Luo, Mona Yiting; Häcker, Irina; Schetelig, Marc F.; Grevelding, Christoph G.; Schroeder, Frank C.; Lau, Gilbert Sei Kung; Taubert, Anja; Rodriguez, Ana; Heine, Andreas; Yeo, Tiong Chia; Grünweller, Arnold; Taroncher-Oldenburg, Gaspar
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Scientific Reports
  • Sprache: Englisch
  • DOI: 10.1038/s41598-023-35765-6
  • ISSN: 2045-2322
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Inhibition of eukaryotic initiation factor 4A has been proposed as a strategy to fight pathogens. Rocaglates exhibit the highest specificities among eIF4A inhibitors, but their anti-pathogenic potential has not been comprehensively assessed across eukaryotes. In silico analysis of the substitution patterns of six eIF4A1 aa residues critical to rocaglate binding, uncovered 35 variants. Molecular docking of eIF4A:RNA:rocaglate complexes, and in vitro thermal shift assays with select recombinantly expressed eIF4A variants, revealed that sensitivity correlated with low inferred binding energies and high melting temperature shifts. In vitro testing with silvestrol validated predicted resistance in <jats:italic>Caenorhabditis</jats:italic><jats:italic>elegans</jats:italic> and <jats:italic>Leishmania</jats:italic><jats:italic>amazonensis</jats:italic> and predicted sensitivity in <jats:italic>Aedes</jats:italic> sp., <jats:italic>Schistosoma</jats:italic><jats:italic>mansoni</jats:italic>, <jats:italic>Trypanosoma</jats:italic><jats:italic>brucei</jats:italic>, <jats:italic>Plasmodium</jats:italic><jats:italic>falciparum</jats:italic>, and <jats:italic>Toxoplasma</jats:italic><jats:italic>gondii</jats:italic>. Our analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens with rocaglates. Finally, our findings might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens.</jats:p>
  • Zugangsstatus: Freier Zugang