Wiebke Obermann, Mohammad Farhan Darin Azri, Leonie Konopka, Nina Schmidt, Francesca Magari, Julian Sherman, Liliana M R Silva, Carlos Hermosilla, Andreas H Ludewig, Hicham Houhou, Simone Haeberlein, Mona Yiting Luo, Irina Häcker, Marc F Schetelig, Christoph G Grevelding, Frank C Schroeder, Gilbert Sei Kung Lau, Anja Taubert, Ana Rodriguez, Andreas Heine, Tiong Chia Yeo, Arnold Grünweller, Gaspar Taroncher-Oldenburg
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...
June 8, 2023: Scientific Reports