Development of a preclinical candidate for Chagas disease that acts through inhibition of Trypanosoma cruzi squalene synthase

Chagas disease is a neglected tropical disease that affects millions of people worldwide. Within Latin America, the region mainly impacted by Chagas disease, it is a leading cause of illness and death. Chagas disease is caused by the parasite Trypanosoma cruzi, a single-cell organism that is spread to people via insects, ingestion, blood transfusions and mother-to-child transmission. While the immune system usually successfully supresses the initial high level of parasites, small numbers of parasites often remain. Infected people may have no symptoms for many years, but for substantial numbers the infection will eventually manifest as a chronic debilitating disease, affecting mainly the heart and gastro-intestinal tract. Over one million people are estimated to suffer from Chagas induced heart disease, leading to over 12,000 deaths annually. The actual death toll is likely much higher due to under-reporting and the temporal separation between infection and symptomatic disease, resulting in many Chagas disease-related deaths likely not being recognised. The global economic impact of the disease is estimated at >$7 billion annually. Two treatments are available (benznidazole and nifurtimox), which share significant drawbacks, in particular toxicity and the need for long treatment regimens (60 days and longer). For treatment to be successful it needs to be started as soon as possible and well before the symptoms of chronic disease arise. The adverse effects caused by current drugs in asymptomatic people pose an important barrier to treatment and lead to frequent treatment discontinuation. New, safe and effective medicines are urgently required, but the drug development pipeline is nearly empty, with few new compounds in late-stage development for Chagas disease. Our goal is to generate new treatments that address the major issues with the current drugs. We have identified a promising new chemical series of T. cruzi inhibitors that act through the parasite enzyme squalene synthase and propose to further develop the series to deliver a preclinical candidate, a key step towards a new treatment for Chagas disease. We discovered this compound series through screening a large collection of compounds for killing activity against T. cruzi parasites. We applied our drug discovery expertise to progress this series and achieved proof-of-concept efficacy in an animal model of chronic Chagas disease. In parallel, a close collaborator determined that the compounds exert their effect through inhibition of T. cruzi squalene synthase (SQS). This enzyme is responsible for the synthesis of squalene, a key lipid for the parasites. Subsequently we expressed and purified T. cruzi SQS and demonstrated that our compounds bind to the enzyme and inhibit its activity. Target identification allows us now to accelerate the development of the series, while proof-of-concept efficacy provides the confidence that we can deliver efficacious compounds. Our team has a track record of delivering preclinical candidates for parasitic diseases, and has the skills required to achieve success, including in parasitology, enzymology, structural biology, medicinal chemistry, computational drug discovery and pharmacokinetics. A new preclinical candidate for Chagas disease will be a key step towards delivery of a new treatment and highly attractive for further funding to support clinical development.