Use of Transporters to Selectively Deliver Agents to Trypanosomes

Lead Research Organisation: University of Dundee
Department Name: Biological Sciences

Abstract

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.

Technical Summary

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.

Publications

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Chollet C (2009) Targeted delivery of compounds to Trypanosoma brucei using the melamine motif. in Bioorganic & medicinal chemistry

 
Description University of Glasgow 
Organisation University of Glasgow
Department Institute of Infection, Immunity and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a joint research project between the Gilbert (Dundee) and Barrett (Glasgow) labs. The collaboration has been on-going for a number of years. This MRC funding was to examine the possibilities of extending their methodology on selective delivery of compounds for sleeping sickness to new classes of potential anti-trypanosomal.
Collaborator Contribution This project was a joint grant between Dundee and Glasgow. The biology was carried out in Glasgow and the chemistry in Dundee. This was an extension of a long-term collaboration in this field between the two research groups (Gilbert/Barrett)
Impact The collaboration on selective delivery of compounds to Trypanosoma brucei has given rise to a number of publications. One paper has resulted from the work funded by the MRC.
 
Title Selective Delivery of Compounds to Trypanosomes 
Description We have previously reported on the selective delivery of compounds to Trypanosoma brucei using the P2 and related transporters. In this project we extended this methodology to new classes of compounds. As a results we discovered compounds with improved activity; however the compounds were not sufficiently potent to take further. 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed No
Impact We have published the data from this study.
 
Title Method for selective delivery to trypanosomes 
Description Further development of a method to selectively deliver compounds to trypanosomes. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2008
Development Status On hold
Impact This is helping us to design novel agents for the potential treatment of trypanosomiasis. Unfortunately the compounds were of insufficient activity to take further.