The Development of Novel Therapeutics Against Schistosomiasis

Abstract

Human schistosomiasis is a neglected tropical disease caused by parasitic worms. It affects over 250 million people globally. Most human infections are caused by S. mansoni, S. haematobium, and S. japonicum. Currently there is only one method of treatment for human schistosomiasis, the drug praziquantel. Constant selection pressure has caused a serious concern for a rise in resistance to praziquantel leading to the necessity for additional pharmaceuticals, with a distinctly different mechanism of action, to be used in combination therapy with praziquantel.Previous treatment of Schistosoma mansoni included the use of oxamniquine (OXA), a prodrug that is enzymatically activated by a Sulfotransferase, an enzyme produced by S. mansoni (SmSULT). Although sulfotransferases are produced by S. haematobium and S. japonicum, OXA is not effective against these two species. By using information from the crystal structure of SmSULT bound to OXA, 250 OXA derivatives were designed and tested in vitro against the adult parasites. We were able to identify effective derivatives that kill Schistosoma mansoni (85%), S. haematobium (40%) and S. japonicum (83%). Recently, we identified CIDD‐149830 as an effective derivative that can kill all three schistosome species (100%) within 7 days in vitro. In vivo studies results show a significant reduction in the number of harvested worms from infected animals after treating them with CIDD‐149830.In this study, we re‐engineered and tested 42 derivatives based on the structure of CIDD‐149830 and we were able to identify CIDD‐0150610 as a very powerful derivative that kills 100 % of Schistosoma mansoni overnight in vitro.Support or Funding InformationR01 AI115691