Rocaglates and pateamines target the DEAD-box RNA helicase eIF4A from Schistosoma mansoni and demonstrate anti-schistosomal activity in vitro

Abstract

Abstract For decades, infections with the parasite Schistosoma mansoni have been treated with praziquantel, the only available drug, which highlights the urgent need of treatment alternatives. Natural compounds including rocaglates from plants of the genus Aglaia and pateamines isolated from the marine sponge Mycale hentscheli have exhibited promising anti-viral, anti-cancer, and anti-pathogenic properties. These compounds target the eukaryotic translation initiation factor 4A (eIF4A), which is a crucial factor for unwinding RNA structures in the 5’-UTR of selected mRNAs, and prevent the unwinding activity of eIF4A, which interferes with protein synthesis. Preliminary data indicated anthelminthic activity of the rocaglate silvestrol against S. mansoni in vitro. In this study, we confirmed the interaction of rocaglates and pateamines with recombinant S. mansoni eIF4A and analyzed the activity of these compounds against adult S. mansoni in vitro. Our findings showed reduced parasite vitality and stem-cell proliferation as well as impaired embryogenesis after rocaglate or pateamine treatment in the nanomolar range. Furthermore, we observed that rocaglate-treated S. mansoni recovered during washout experiments, while pateamine treatment displayed irreversible effects finally killing most of the worms. Although some properties of the used compounds impede their suitability as anti-schistosomal candidates, eIF4A remains a promising drug target in this parasite.