Trypanosomatid protein synthesis as a target for novel drug therapies

Trypanosomatids are eukaryotic parasites that migrate between insect vectors and mammalian hosts. They cause a number of highly debilitating and potentially fatal zoonotic diseases with major impacts on human health (and life-span) on a global scale. Trypanosoma cruzi, which causes Chagas disease, is believed to affect approximately 11 million people in Mexico, Central America and South America. There is currently no vaccine against Chagas disease, and the available antiparasitic treatments are unpleasant and not fully effective. Moreover, resistance to the commonly used azole- and nitro- derivative drugs is rising. Leishmania is spread by sandflies in South America, southern Europe, the Middle East, Asia and Africa, and causes three types of disease (cutaneous, mucocutaneous and visceral leishmaniasis) in approximately 12 million people. Many of the drugs used against Leishmania have side effects, and resistance is on the increase. In this project, we propose to investigate the feasibility of pursuing a new route to developing drugs effective against these dangerous parasites. This route involves differential targeting of the protein synthesis machinery in the parasite so that the human (or animal) host is unaffected.

Over the two years of this project we expect to achieve a significantly enhanced level of understanding of important targets for drugs in trypanosomatids and also to have identified some candidate drugs that can be incorporated into trials in animals subsequent to this study.

This project seeks to take advantage of differences between the translation machineries found in trypanosomatids and those in mammals as a basis for identifying/developing inhibitor molecules that selectively inhibit protein synthesis in the parasite cells. We will start from a strong base of relevant preliminary data and relevant expertise.

In trypanosomatids, the interactions between the translation factors eIF4E and eIF4G utilise different binding motifs to those used in mammalian cells. In addition, both Leishmania and T.cruzi manifest direct interactions between eIF4E and poly(A)binding protein (PABP), a type of interaction that has not been identified in mammalian cells. These distinct interaction types will be characterised using biophysical methods including surface plasmon resonance and isothermal calorimetry, and we will also perform structural studies wherever possible. There have previously been multiple successes with structural work on similar translation factors in a number of organisms, and we therefore expect to be able to obtain useful structural data here as well. This will not be critical to the success of the project, but will accelerate progress on rational aspects of drug development.

The primarily molecular studies in Warwick and Leeds will be paralleled by cellular investigations in Curitiba. The excellent complementarity between the expertise and skills in the respective locations is a very positive feature of this project, and will result in rapid progress towards useful outcomes. By working directly with trypanosomatid cultures the Brazilian colleagues will be able to obtain detailed insight into the roles of our translation factor targets in vivo, and into the impact that candidate drugs have on these targets and thus on the viability, infectivity and differentiation capability of the trypanosomatid parasites.

This work will have multiple beneficiaries.

By developing new candidate drugs against trypanosomatid diseases, the project will establish a platform for generating potential benefit for large numbers of the wider community in Brazil (and elsewhere) who suffer the debilitating effects of trypanosomatid infections. Any drugs that ultimately emerge as a result of this work could improve the lives of many people.

Progress towards developing effective anti-trypanosomatid drugs will be welcomed by governments and charities alike, since these will anticipate the future arrival of powerful tools they can apply to tackle serious diseases.

Any progress towards eliminating the scourge of trypanosomatid-related diseases will establish the potential for improving the health and economic status of communities in affected regions.

It is widely appreciated that the trialling of new drugs in humans is an expensive and long-winded process. However, a notable feature of zoonotic diseases is that there is potential to achieve at least some progress towards lessening their negative impact on humans by tackling trypanosomatid infections in animal vectors. In Brazil, dogs harbour a sizeable pool of trypanosomatid parasites which can be transferred to humans via insect vectors. Trialling candidate drugs in animals could therefore offer the prospect of achieving significant improvements in public health via indirect treatments that would take less time to implement than if using direct human therapies.

We believe that three to four years from the start of this project would be a realistic timescale for trials in dogs to be initiated in Brazil (although such trials would be planned and performed after the completion of the present project.

Researchers working on this project will acquire a wide range of skills relevant to the development of drugs targeted to human disease agents, including small molecule screening, rational drug design, analytical tools for characterisation of drug-target interactions, and characterisation of drug impacts on target organisms. All of these skills will be of value in jobs in wider academia and in a wide range of industrial environments.