More than 200 million people in sub-Saharan Africa are infected with schistosomiasis, a parasitic worm disease that kills 300,000 people each year, and the only drug available to treat it has serious shortcomings. Praziquantel kills adult worms but leaves juvenile worms alive, forcing patients to be retreated and raising costs for mass-treatment programmes. There are also growing reports of treatment failure, raising fears that drug-resistant parasites could leave doctors with no effective medicine at all. The tablets are large and bitter, making them difficult for children to swallow. The researchers have developed a new laboratory test that can rapidly screen thousands of chemical compounds against the parasite’s larvae, juvenile, and adult stages at once. They will use this test to search a large pharmaceutical company’s proprietary compound library, along with commercial inhibitor collections never before tested against schistosomiasis. A not-for-profit drug discovery organisation will then refine the most promising molecules into an oral drug candidate that works against all stages of the infection. If successful, this project could produce a replacement for praziquantel that is safer for children, requires fewer doses, and remains effective even if resistance emerges.
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Schistosomiasis is a severe helminthic disease affecting over 200 million people mainly in poor countries of sub-saharan Africa and resulting in 300,000 deaths per year. Treatment relies on a single drug, praziquantel (PZQ), but this is not ideal since: (i) PZQ kills adult worms but not juvenile worms developing in the body and so cure requires patients to be retreated which adds to cost and undermines efforts to control the level of disease by mass treatment of schoolchildren or communities (ii) emergence of resistance is a major concern following several reports of treatment failure. Spread of such resistance would leave us without a single drug to treat and control this disease (iii) PZQ is sub-optimal for paediatric since the tablets are large and the drug bitter which often causes choking. Since the development of PZQ and its implementation in the 1980s pharmaceutical companies have stopped schistosome drug discovery and there has been limited interest in development of alternative drugs, even in academic institutions. PZQ and earlier anti-schistosome drugs were discovered by testing in mouse models of the disease run by pharma which is a very slow and costly process for discovery of promising chemical structures. Our recent development of an in vitro High throughput screen (HTS) to identify drug effects using in vitro derived Schistosoma mansoni larvae allows, for the first time, screening of the large compound collections put together by pharma and academic institutions as resources for drug discovery. Our aim is to develop a clinical candidate better than PZQ notably in being active against all intra-mammalian stages. The in vitro screening sequence (larval HTS/juvenile worms/adult worms/cytotoxicity) will identify compounds active against all stages of the important human schistosome species and with promising parasite/cytotoxicity profiles. Salvensis, our collaborator, has agreement from a large pharmaceutical company to access a refined subset of its proprietary compound file. In addition we have large collections of commercially available inhibitors, never before tested for schistosomiasis activity, available for this project. Funding is sought to bridge the translational gaps in NTD drug discovery between academia and pharma and between large compound collections and the first available HTS for schistosome drug discovery. In addition to the file, Salvensis, a not-for-profit organisation based on >50 years experience in pharma drug discovery, is able to access pharma tools and information, greatly facilitating NTD drug discovery. LSHTM and Salvensis will use carefully selected medicinal chemists to synthesize analogues of the most promising molecules from our in vitro assays in order to identify the best series and optimise them, through a series of milestones, to an oral clinical candidate which we will aim to license for clinical development.
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