Authors

J Forde-Thomas¹; H Whiteland¹; B Baragana³; M Kiczun²; I Gilbert³; K F Hoffmann¹;  ¹ Aberystwyth University, UK;  ² Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, UK;  ³ University of Dundee, UK

Discussion

Schistosoma mansoni is a parasitic trematode that contributes to the infectious human disease schistosomiasis which affects in excess of 240 million people worldwide. Currently a single chemotherapeutic agent, praziquantel (PZQ), has been identified to combat this disease. However, PZQ is ineffective against juvenile worms, often necessitating repeated treatment. With no anti-Schistosoma vaccine on the horizon, mass drug administration programs form the only line of defence in controlling this disease.

This project is focused on identifying novel chemotypes with anti-schistosomal activity. Our workflow initially screens compounds against schistosomula larvae using our automated high-throughput platform (Roboworm). Hits from these larval screens are subsequently taken forward for screening against juvenile and adult worms.

We initially screened 12,672 compounds from the Global Health Chemical Diversity Library (GHCDL) against schistosomula and identified 214 hits. These initial hits were reconfirmed and the chemical space around these hits expanded in a second round of screening against larval stage schistosomula. Confirmed hits were then subjected to mass spectrometry analysis and 9 compounds were ultimately taken forward for testing in juvenile and adult worms.

Juvenile and adult worms screens were conducted in parallel at a single point concentration of 20mM. Against juvenile worms, 2 out of the 9 compounds were hits. Upon titration, these two hits continued to show significant activity down to 5mM.
Of the 9 identified hit compounds, 3 were also hits against the adult worms. However, 2 of these demonstrated differential activity towards male and female worms. Only one compound was found to have activity against both sexes at 20mM. This hit was also one of the compounds effective against juvenile worms.

These initial results represent promising progress in the development of a new treatment options for this disease.