A group of parasites called Kinetoplastida, is responsible for three neglected tropical diseases: leishmaniasis, Chagas disease and human African trypanosomiasis (HAT, or African sleeping sickness) caused by various Leishmania species, Trypanosoma cruzi, and Trypanosoma brucei, respectively. HAT has been greatly reduced by a successful WHO campaign with an average of less than 1000 cases declared annually, but the impact of other Kinetoplastida on public health remains high. Approximately 1.3 million new cases of leishmaniasis are reported annually (mortality rate 30,000 p.a.). Similarly, there are ~8 million Chagas disease sufferers worldwide caused by T. cruzi with reported mortality and morbidity rates ~0.025 and ~30% respectively and over 65 million people at risk.
Treatment of leishmaniasis relies on a small number of drugs which are toxic to the host, expensive
and/or difficult to administer. Two drugs are available for treatment of Chagas disease but treatments for T. cruzi have low cure rates once the infection passes from the initial acute phase to the chronic state. The existing approved treatments for kinetoplastid diseases are widely recognised as being inadequate.
This project was an early-stage drug discovery program aiming to establish test-tube screening materials and methods, followed by library screening and hit expansion to produce inhibitors of our targets that could be used in later stage drug discovery efforts. Our target enzymes are Flap endonucleases (FENs) which process the branched DNA structures (5’ flaps) arising during DNA replication. FENs are found as independent globular proteins in eukaryotes, including parasites from this study. Inhibiting FEN enzymes in any organism tested so far will lead to organism death. Specific inhibitors with good pharmacological properties, i.e. not toxic to humans, cheap to produce and with good bioavailability in vivo, would thus make potential antiparasitic drugs.
