Buffalo BioLabs INC has synthesized a series of novel anti-trypanosome compounds with nanomolar activity against whole cells. After oral administration to mice, the Curaxin drugs reach tens of micromolar concentration in mouse blood, exceeding by 300-fold the amount needed to kill all bloodstream Trypanosoma brucei in culture. Thus the potential for these novel drugs to cure T. brucei-infected mice is immense. Therefore, we will test the ability of three lead Curaxins to cure T. brucei-infected mice, using models of both acute form and chronic stage human African trypanosomiasis (HAT). Proteins that bind Curaxins in the African trypanosome have not been identified. To further our understanding of how Curaxins kill T. brucei, and to prepare the stage for further optimization of the Curaxin scaffold by ligand-assisted drug design, we will concentrate Curaxin- binding proteins by affinity chromatography and identify them by discovery mass-spectrometry. Finally, the biologically relevant target(s) of Curaxin will be identified by determining the effect of the drug on biochemical activities of the Curaxin-binding proteins from the trypanosome.
New drugs are needed for treatment of human African trypanosomiasis. The studies described in this proposal evaluate the possible of using Curaxins, are orally bioavailable drugs, as treatment of HAT in a mouse model of the disease. Attempts are also made to identify the targets of Curaxins, which are effective in nanomolar concentrations against cultured bloodstream T. brucei.