Preclinical Testing of Potential Next-generation Antischistosomal Compounds - PROJECT SUMMARY / ABSTRACT Human schistosomiasis is a disease caused by species of the genus Schistosoma, which globally affects over 200 million people. The major species affecting humans are: S. mansoni, S. haematobium, and S. japonicum. There is currently only one method of treatment (monotherapy), the drug Praziquantel (PZQ). Constant selection pressure through mass chemotherapy – this year alone will see the administration of over 250 million doses – has yielded evidence of resistance to PZQ. This has been observed in both the laboratory and field. The goal of this research is to develop a second drug with a different mode of action for use in conjunction with PZQ to improve the efficacy of treatment and mitigate resistance. Previous treatment of S. mansoni included, among others, the use of oxamniquine (OXA), a prodrug that is taken up by the schistosome and enzymatically activated within S.mansoni but is ineffective against S. haematobium and S. japonicum. The OXA activating enzyme was identified as a sulfotransferase (SmSULT). The focus of this research was to reengineer OXA to be more effective against S. mansoni and effective against S. haematobium and S. japonicum. We employed an iterative process in which structural data is used to inform compound design and chemical synthesis of derivatives, which are then tested in an in vitro killing assay. The compounds that are best killers are soaked into new crystals and the process repeated. Over 350 OXA derivatives have been synthesized including CIDD- 0150303 that will kill 100% S. mansoni, S. haematobium and S. japonicum in an in vitro assay. This derivative also will kill a significant number of schistosomes in an in vivo model of schistosomiasis. We propose to optimize the leading/top derivative to improve solubility, bioavailability, prolong it’s action and perform safety and toxicity studies. These studies will also include determining the physical chemical properties of the derivative and improvement of desirable drug properties. An additional major focus will be on the impact of combination therapy with PZQ. The outcome of the proposed studies will be a novel drug that in combination with PZQ will have a significant impact on global human health and will lead to improved treatments for Schistosoma to reduce the morbidity, morality, and transmission rates associated with schistosomiasis. The Major deliverable will be an OXA derivative that results in a new anthelmintic candidate ready for formulation, scale-up, and clinical studies.
