Schistosomes infect 200 million of the world’s poorest people. Although these parasites kill
250,000 people annually, and rob millions more the ability to lead healthy and productive
lives, treatment of schistosome infection relies on a single drug (Praziquantel). Unfortunately,
Praziquantel is not a magic bullet. Indeed, praziquantel is not equally effective against all
intramammalian stages of the parasite’s life cycle and it suffers from a variable cure rate in
some endemic settings. This later point, raises the specter that praziquantel-resistant
parasites could emerge as organizations ramp up mass drug administration programs.
Indeed, several studies have demonstrated that strains with reduced sensitivity to
praziquantel can be rapidly selected in the laboratory. Therefore, efforts to develop the next
generation of antischistosome therapies to replace praziquantel are key to a sustained effort
to eradicate this disease. Drug development efforts against schistosomes suffer from two
important limitations. First, the large size of the adult parasites (~1cm in length) makes
screening thousands of compounds for activity against the worm impractical. The second
important limitation is that we only know the function of a small number of proteins in these
worms making it challenging conduct informed target-based drug discovery efforts. To
address these issues, we have conducted the first large-scale loss-of-function RNA
interference (RNAi) screen in adult schistosomes. Using this platform, we have performed
over 2000 individual RNAi knockdown experiments in adult Schistosoma mansoni and
identified nearly two hundred genes, a large fraction of which are potentially druggable, that
are essential for parasite survival and/or neuromuscular function both in vitro and in vivo
inside mice. To capitalize on these studies we will execute three specific aims to discover
and experimentally prioritize druggable targets in the schistosome. In Specific Aim 1, we will
utilize RNAi and in silico approaches to identify and prioritize druggable targets that are
essential in vitro and in vivo in three medically relevant schistosome species. In Specific Aim
2, we will experimentally validate the druggability of the highest priority targets from Aim 1 by
assessing the performance of these targets in small-scale high throughput small molecule
screens. These studies will identify both validated druggable targets in the schistosome that
can form the basis of future drug discovery campaigns and compounds poised for lead
optimization efforts.