Structure- based inhibitor design for key enzymes of Tryposoma brucei

Abstract

Human African trypanosomiasis (HAT) also known as sleeping sickness is caused by a subspecies of Trypanosoma brucei. These parasites are transmitted by tsetse flies and endanger over 60 million people in Sub-Saharan Africa. Untreated, sleeping sickness is fatal, causing at least 48.000 deaths per year. Its treatment remains complicated since the currently available drugs show high toxicity and are too expensive to be ubiquitously distributed in the affected third world economies. Additionally, emerging drug resistance towards the most clinically relevant anti HAT drugs, drastically limits treatment options and makes it imperative to conduct research to find safer and more efficient drugs to treat this terrible disease.
This thesis describes the hit identification and hit validation for two validated
targets for HAT: Tb6PGDH and TbUGP. For hit identification different techniques like in silico virtual screening, NMR lead-like fragment screening and HTS were used. For TbUGP a very first drug-like, competitive inhibitor with a pIC50 of 3.53±0.04 and a Hill slope of 1.1±0.1 was discovered. Additionally this thesis describes the determination and validation of the in silico proposed binding mode using mutation studies and crystallisation techniques.