Introduction and Background of the Project

Introduction:

Chagas disease is a life-threatening disease caused by the protozoan Trypanosoma cruzi (T. cruzi) and is a major cause of mortality and morbidity in Latin America, where it affects over 6 million people. Since the elucidation of the etiology of the disease by the Brazilian physician Dr Carlos Chagas in 1909 who was first to report the presence of flagellated protozoan Trypanosoma cruzi in humans only two treatments - benznidazole and nifurtimox – have been made available to patients. Both of them have significant drawbacks to limit their use: long treatment periods (60-90 days), serious side effects, a high drop-out rate of patients due to side effects and they have not been proven effective in people with severe chronic symptoms. There is no vaccine available to date, and treatment of Chagas disease relies on chemotherapy. New field-friendly (shorter-course and oral) therapeutic agents with high levels of efficacy and safety are therefore needed

Project objective

The main objective of our proposed project is to identify novel T. cruzi active scaffolds meeting GHIT/DNDi hit criteria and amenable for further development by screening microbial cultured broths with a natural product chemistry approach. We aim at characterizing at least five T. new chemical templates unprecedently associated with T. cruzi activity over an 18-month work period. We will also opportunistically evaluate the anti-Leishmania donovani activity of any antichagasic agent to be identified in the course of the project.

Project design

In this project, three academic institutions (Kitasato University, Nagasaki University, and the University of Tokyo) and DNDi will utilize their expertise to identify at least five seed compounds for Chagas disease therapeutics produced by microorganisms in a one-and-a-half-year research period. The seed compounds for Chagas disease therapeutics to be identified during the project will also be assessed for their activity against Leishmania donovani, which causes visceral leishmaniasis, to verify their drug potential.

How can your partnership (project) address global health challenges?

It is hoped that development research based on the seed compounds for Chagas disease therapeutic to be found in this project will lead to the development of new drugs that are highly effective and safe and can be treated with short oral doses, thereby providing new treatment options for patients suffering from Chagas disease. 

What sort of innovation are you bringing in your project?

Screening for Chagas disease therapeutic seed compounds has been carried out from several discovery sources. However, natural product chemistry from microbial culture media has rarely been used because of the need to undergo a complicated process of repeated purification and activity evaluation. The main feature of this project is that it will search for therapeutic drug seeds for Chagas disease from unexplored microbial culture media in collaboration with the high-throughput evaluation system of Nagasaki University.

Role and Responsibility of Each Partner

Kitasato University is responsible for preparing microbial culture broths, re-cultureing microorganisms that have passed screening, purifying seed compounds from the culture media for the treatment of Chagas disease, and determining its structure.

Nagasaki University is responsible for evaluating the activity against T. cruzi (the protozoa causing Chagas disease) of the microbial cultured broths, purified fractions, and seed compounds prepared by Kitasato University.

The University of Tokyo is responsible for evaluating the activity against L. donovani (the protozoa causing visceral Leishmania) and testing the potentials of seed compounds prepared by Kitasato University as a treatment for visceral Leishmania.

DNDi will play an advisory role, managing project progress, analyzing data, and prioritizing hits to support the development of seed compounds.