Grant: Project Grant

Neglected tropical diseases (NTDs) due to protozoan infections are chronic, debilitating, and poverty-promoting maladies. Current treatments are failing due to spreading resistant strains, host toxicity, and incompatibility with rural health systems. Among NTDs, pathogenic trypanosomatids [T. cruzi (Chagas disease), T. brucei (HAT) and Leishmania spp.] are responsible for the most dramatic consequences. HAT is endemic in sub-Saharan Africa and leads to a chronic stage, which without treatment progresses to death. No cure exists for Chagas disease and drugs are effective for only 50% of early cases. Resistant strains of Leishmania are spreading due to a vacuum of therapeutic alternatives, with the few effective medications being compromised by parenteral administration and toxicity. The gravity of the NTD situation necessitates a new mindset to provide effective therapy. Armed with new biomedical technology, our collaboration has created novel leads and strategies for target validation to address two proposed objectives: 1) Identifying new points of therapeutic intervention with promising prototypes, we will probe primary and secondary targets, binding patterns, modes of action and mechanisms of resistance. 2) Targeting vital parasite functions, we will conceive new agents to disrupt glycosome and ribosome function. Novel therapy to treat resistant NTDs will be developed with improved potency, selectivity and drug-like properties. Our interdisciplinary team is strategically composed of international leaders in the fields of chemistry, molecular and medical parasitology, and structural biology. Highly qualified personnel will train in the identification and targeting of new points of intervention against parasites. Fueled by a track record for success, promising leads and collaborative results, our team is positioned to pioneer discovery of original tactics for controlling parasitic infection and novel therapy to relieve the socioeconomic burden of NTDs.