Use of Transporters to Selectively Deliver Agents to Trypanosomes

Human African trypanosomiasis (HAT), more commonly known as sleeping sickness is prevalent in sub-Saharan Africa and is inevitably fatal unless treated. It is caused by single-celled parasites, which live in the blood stream and eventually invade the brain. The current drugs available to treat the disease are unsatisfactory, due to issues such as toxicity, resistance, difficulty in administration of the drugs, lack of efficacy and cost. In this basic science proposal we aim to start the development of new drugs. The parasites which cause HAT require nutrients from the human host for their survival. To take up these nutrients, they have transporters in their cell membranes. Some of these transporters are very different from those found in human cell membranes. One particular transporter, usually involved in carrying important chemicals called purines into cells, can be tricked into carrying other classes of molecules (transporter motifs), which are not carried by mammalian purine transporters. We aim to develop new classes of drugs to treat HAT by attaching compounds that will kill parasites to these transporter motifs. These compounds should then selectively kill the parasites. The project will consist of design and preparation of these compounds, evaluation and studying how the compounds work.

The parasites which give rise to Human African Trypanosomiasis (HAT) have a requirement for nutrients from the host. To enable this, trypanosomes have specific transporters, some of which have unusual substrate specificities. For example, it has been established that melamine and benzamidine derivatives, including some current drugs, are selectively concentrated in the parasite by the P2 aminopurine transporter and some other carriers. We have been interested in using these transporters to selectively concentrate trypanocidal toxins in the parasite. By attaching melamine moieities to trypanocidal compounds we have had significant success using this strategy. In this proposal, we wish to extend this approach to consider the delivery of new classes of compound to the parasite and to attach compounds to the benzamidine moiety as well. The project will consist of preparation of compounds and then analysis of these compounds for uptake into the parasite, trypanocidal activity, mode of action and resistance studies.