Yongjun Dang

Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

eIF4A is not only related to tumorigenesis and prognosis, but also the target ofnatural product, pateamine A, suggesting that eIF4AI is a potential drug targetfor tumor therapy. However, the internal catalytic mechanism of ATPase and RNAhelicase of eIF4A remains unclear, which prevents the understanding of thebiological function of eIF4AI and clinical application as a therapeutic target. Inaddition, all known inhibitors of eIF4AI were isolated from natural resources andtheir complex structures make them difficult to be synthesized for the structuraloptimization and future pre-clinical research. Through multidisciplinary approachs, we found thatthe speed of Pi release will possibly determine the conformation change andcoupling between ATPase and Helicase of eIF4AI.  At same time, the binding site of PatA werepredicted through molecular docking and partially confirmed by the enzymatic assayin vitro.  One leucine mutation at linker region of two domains of eIF4A can cause the resistance to the known inhibitors of eIF4A. By taking advantage of this mutant, we identified a novel inhibitor of eIF4A with completely different mechanism through screening the in-house natural compound library.  We validate that the action of the compound is through binding to eIF4A in vitro and in vivo to inhibit protein translation initiation. The potential clinical application in tumor therapy will be explored in animal model as well.