Schistosomiasis is a serious global health problem caused by intravascular parasitic worms called schistosomes. Currently ~200 million people are infected with these parasites. Tens of millions of people have chronic morbidity and new treatments are needed. We have identified an acetylcholinesterase enzyme (SmT-AChE) that is an accessible and rational target of such treatment. The enzyme is expressed on the surface of intravascular stage schistosomes. Parasites with diminished SmT-AChE (achieved through RNAi) fail to establish a robust infection in mice. Chemical compounds that mimic the RNAi effect and inhibit SmT-AChE should likewise debilitate the worms. AChEs are extremely druggable proteins and several drugs that target vertebrate AChE isoforms are currently used to treat a number of conditions in humans.
The aim of this application is to identify potent and specific SmT-AChE inhibitors to test the hypothesis that these can form the basis for a novel anti-schistosome therapy. We intend to apply one of the key technologies in modern drug discovery ? high throughput screening (HTS) - to the neglected tropical disease, schistosomiasis. To facilitate this aim we have expressed SmT-AChE as a secreted recombinant protein in a mammalian expression system and we have purified the active enzyme from the medium. AChE activity is measured using a simple colorimetric assay. With collaborators at the Broad Institute of MIT and Harvard, we have performed a small-scale screen of the MLPCN (Molecular Libraries Probe Production Centers Network) Validation Library containing 1,894 compounds and we have identified a small number of SmT-AChE inhibitors of variable efficacy. In this application, we aim to build upon this successful pilot study by undertaking a validated High Throughput Screen of 100,000 compounds to identify those that inhibit SmT-AChE. Differential, cytotoxicity and secondary screens will then be employed to identify the most potent, specific and safe compounds that could form the basis of a new therapy for schistosomiasis, a condition that today remains a major cause of death and debility around the world.
Schistosomiasis is a major tropical disease caused by parasitic flatworms called schistosomes (commonly known as blood flukes). Our aim in this project is to identify a new drug that can block a newly described, essential parasite enzyme and therefore serve as a novel, effective treatment for the disease.
