Authors

K Lees¹; JE Forde-Thomas¹; MG Taylor²; E Holmes²; R Street-Jeakings²; BJ Hulme¹; M Evans¹; B Dankwa¹; N Caldwell²; B Baragaña²; IH Gilbert²; KF Hoffmann¹;  ¹ Aberystwyth University, UK;  ² Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, UK

Discussion

Schistosomiasisis a neglected tropical disease caused by blood flukes of the genus Schistosoma. This parasitic trematode currently infects over 200 million people worldwide, resulting in around 12,000 deaths annually. At present, Praziquantel is the only drug available to treat schistosomiasis. However, it is ineffective against the juvenile stages of the parasite, necessitating multiple treatments. With no anti-Schistosoma vaccine on the horizon, mass drug administration programs form the predominant line of defence in controlling this disease. Therefore, new drugs are desperately needed.

To identify novel chemicals with anti-schistosomal action, we collaborate closely with our partners at the Drug Discovery Unit in Dundee. One approach we employ to identify prospective therapeutic leads is to screen pre-existing compound libraries. The KCGS Protein Kinase Set (v1) is one such library that contains 187 inhibitors of 215 human kinases. These 187 compounds were initially tested at a single point concentration (10 µM) on our automated high-throughput platform (Roboworm) against Schistosoma mansoni schistosomula. There were 26 hits from this initial screen. Compounds with pan-kinase effects (e.g. targeting 5 or more human kinases) or with published cell toxicity data were discarded. The remaining 15 compounds were purchased (where possible), resynthesized by Dundee or re-supplied by SGC for validation and titration studies in schistosomula and adult worms. To investigate the wider chemical series of the 15 hits, commercial analogues were acquired for further phenotypic screening and DMPK analysis. Hit-to-lead studies are now being undertaken for multiple chemical series.