Introduction and Background of the Project

1. Introduction

Chagas also known as American trypanosomiasis is a live-threatening infectious disease caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), affecting more than 10 million of people, mainly in Latin America. However, due to human migration, this disease can be found in Europe, Oceania and also in Japan. The disease is primarily transmitted by the triatomine bugs’ faeces excreted during blood feeding. The disease can also be transmitted by contaminated blood transfusion, organ transplantation, and from mother to child during childbirth and breastfeeding. Symptoms of the initial phase of the Chagas disease include flu-like symptoms and it could be unnoticed, however if not treated, it can progress to a chronic stage where it leads to serious heart and gastrointestinal complications and eventually death.

2. Project objective

The main objective of this research project is to identify novel and potent antichagasic compounds from selected chemical library subsets from the Center for Supporting Drug Discovery and Life Science Research, Osaka University that meets the GHIT/DNDi criteria (1).

3. Project design

A total of seven chemical library subsets from the Center for Supporting Drug Discovery and Life Science Research, Osaka University (Osaka Library, total number 62,029 compounds) will be tested in a cell-based high-throughput screening system against intracellular amastigote stage of a T. cruzi strain that were genetically engineered to express the firefly luciferase gene. The cytotoxicity against human cell lines as well as the biological activity against four major T. cruzi strains of the primary hits will be evaluated.

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

Chagas is one of the neglected tropical diseases that historically received limited attention and funding for drug development. Despite the discovery of Chagas disease since 1909, still there are only two medications (benznidazole and nifurtimox) for the treatment of the disease with limited efficacy in the chronic stage, and few compounds in the developmental pipeline. We aim to discover novel hits series with pertinent mechanisms of action that would potentially be developed into novel effective and safe drugs to combat Chagas disease.

What sort of innovation are you bringing in your project?

In the past, one of the challenges in Chagas drug discovery field was the lack of sensitive drug screening tools. Here we took advantages of the recent advance in the genetic engineering of T. cruzi parasite and established transgenic T. cruzi parasites (four genetically different reference strains) expressing luciferase which will facilitate rapid and accurate evaluation of active compounds in cell-based assay systems. Additionally the screening libraries from Osaka University which will be evaluated in this project have not been assayed against T. cruzi parasite, the causative agent responsible for Chagas disease, and we therefore anticipate novel antichagasic series will be identified from this collaboration.

Role and Responsibility of Each Partner

To ensure effective project management, and successful outcomes, a screening collaboration agreement has been established between Nagasaki University (NU) and Drugs for Neglected Diseases initiative (DNDi), where at NU, Prof. Daniel Inaoka’s group will conduct the HTS, which has been already established and validated, as well as data analysis and interpretation, report writing and collaboration with other partners of the joint research. DNDi will provide coordination and support to initiate the project as well as, data analysis and hit prioritization support to the project.

Others (including references if necessary)

(1) https://dndi.org/scientific-articles/2015/hit-lead-infectious-diseases-nature-2015