Sophie Welsch (Gießen / DE), Francesca Magari (Marburg / DE), Dr. Simone Häberlein (Gießen / DE), Prof. Dr. Arnold Grünweller (Marburg / DE), Prof. Christoph G. Grevelding (Gießen / DE)
Abstract text
Introduction:
Schistosomiasis is caused by an infection with blood flukes of the genus Schistosoma, with S. mansoni being one of several species infectious for humans. No vaccine exists, and treatment of schistosomiasis relies on a single drug - Praziquantel. There is justified fear for the development of resistance, encouraging the search for new targets and drugs.
One potential new drug target is the eukaryotic translation initiation factor 4A (eIF4A), an RNA helicase that unwinds stable RNA secondary structures in the 5'-untranslated region of mRNAs. Once the secondary structures are dissolved, ribosomes can access the mRNA and initiate protein synthesis.
Rocaglates, a compound class isolated from plants of the genus Aglaia, prevent ribosome binding and thus protein synthesis by inhibiting eIF4A. Thereby, rocaglates clamp the mRNA on the surface of eIF4A by interacting with a specific phenylalanine (Phe163) of human eIF4A.
Objectives:
We aim to investigate the functions of schistosomal eIF4A and to clarify whether targeting eIF4A of S. mansoni by rocaglates could be a therapeutic option in the future.
Material & Methods:
Adult S. mansoni worms were treated with rocaglates in vitro. Effects of the treatment on stem cell proliferation were analyzed by an EdU assay.
Two schistosomal eIF4A isoforms, one with the specific Phe and one without, were cloned and recombinantly expressed in Escherichia coli, purified by affinity chromatography, and used for a thermal shift assay to validate the interaction of rocaglates and schistosomal eIF4A.
Results:
Treatment of adult S. mansoni with rocaglates resulted in a reduced vitality and decreased numbers of proliferating EdU-positive cells. First thermal shift assays indicate that only the Phe-containing isoform can be bound by natural and synthetic rocaglates.
Conclusion:
Schistosomal eIF4A may play a role for proliferating cells in adult S. mansoni. The interaction of rocaglates and the Phe-containing isoform as well as the vitality effects of these plant-derived products on S. mansoni motivate for further evaluation of schistosome helicases as potential targets.