A Drug Delivery Strategy for Trypanosomiasis

African sleeping sickness is a disease caused by an infection of eukaryotic pathogens called trypanosomes.  The disease is endemic to sub-Saharan Africa with the potential to affect millions of people. Although a few treatments for the disease have existed for fifty years, many are characterized by poor efficacy or severe adverse side-effects. Bloodstream form (BSF) Trypanosoma brucei generate ATP solely by glycolysis. Previous efforts have revealed two drug scaffolds, the isobenzoselenazolinones and benzamidobenzoic acids,  to be potent in vitro inhibitors of a hexokinase, TbHK1, which initiates the glycolysis cascade in BSF parasites. Nevertheless, this potent in vitro inhibition of hexokinases does not always translate into an effective trypanocide, presumably due to poor cellular permeability or failure to localize into the cellular subcompartment that houses glycolysis in the trypanosome, the glycosome.  The talk will describe our efforts to develop a strategy for overcoming this limitation by the  conjugation of a drug candidate to a tripeptide peroxisome targeting sequence (PTS) that facilitates delivery of molecular cargo to the glycosome.  In doing so, we demonstrate that the poor trypanocidal activity of a potent in vitro TbHK1 inhibitor can be rescued, generating a low micromolar trypanocide.  Further, we demonstrate that fluorescently labeled PTS-drug conjugates localize in the glycosome of live T. brucei.