Through this pilot project, the solution backbone structure of T. brucei's major cathepsin L will be assigned using NMR, and the solution structure of T. brucei's major cathepsin L will be solved. Also, we will characterize rhodesain inhibitory agents from natural product extracts in addition to synthesizing novel derivatives of known low micromolar range inhibitors of rhodesian. Assigning the backbone structure of rhodesain will enable solution-based screening of inhibitors and also facilitate the optimization of known inhibitors so that they can have higher specificity and improved potency, and potentially serve as leads for novel antitrypanosomal drugs. Neglected tropical diseases impact over 1 billion of the world's population predominantly in Asia, Africa and South America and these diseases pose significant threat to global public health including the United States. Thus, continued effort to eradicate and provide treatment options for these diseases remain crucial. Human African Trypanosomiasis, caused by Trypanosoma brucei, is a major threat to public health in sub-Saharan Africa. Human African Trypanosomiasis is a neglected tropical disease and is a disease that the current chemotherapies are largely toxic. There remains a critical need for continued research towards the development of better and safer antitrypanosomal drugs. Several drug targets have been characterized from T. brucei in the last decade and one of the most promising and validated drug targets in this parasite is the cathepsin-L like protease rhodesain. The realization of the aims for this pilot project will add to the knowledge of structurl features important for rhodesain inhibition as well as provide new chemotypes that can be explored for antitrypanosomal drug discovery.