Lead


Lay summary
All endoparasites scavenge nutrients from their host. The study of a parasites' nutrient transporters will reveal how it has adapted to life within a host, and it may also disclose vulnerable points for chemotherapeutic attack. On the one hand, transporters may be drug targets themselves if they are essential for parasite nutrition; on the other hand, transporters may be exploited to specifically target drugs into the parasite via pathways that are absent in the host. Here we aim to identify, characterize, and pharmacologically evaluate nutrient transporter families from Trypanosoma brucei ssp., the causative agents of sleeping sickness and nagana. Research on nutrient uptake by trypanosomes has so far concentrated mainly on transporters of purines, pyrimidines, and sugars. Here we are focusing on other transporter families that bear physiological significance and pharmacological potential: amino acid permeases, transporters of lipid precursors, ion channels, and ABC transporters.Computational prediction of transporters from T. brucei, comparative genomics, and transcriptomics will form the basis for selection of candidate transporters for experimental investigation. Functional characterization of trypanosomal transporters will be carried out by expression in the yeast Saccharomyces cerevisiae and in Xenopus laevis oocytes, with particular emphasis on potential inhibitors and toxic substrates. The physiological role and pharmacological potential of the identified transporters in bloodstream-form T. brucei will be addressed by reverse genetics. This joint effort will promote the understanding of parasite metabolism and open new chemotherapeutic strategies against African trypanosomes.