Introduction and Background of the Project

Introduction

Chagas disease, also known as American trypanosomiasis, is a life-threatening disease caused by the T. cruzi parasite, which is spread mainly by the bite of the ‘kissing bug’. Although Chagas disease can go unnoticed for years, it can eventually cause irreversible damage to the heart and other vital organs. In Latin America, where it is endemic in 21 countries, Chagas disease causes more deaths than any other parasitic disease. The World Health Organization estimates there are over 6 million people living with the disease, presenting an important public health problem in endemic countries – and increasingly in non-endemic countries due to human migration, climate change, and deforestation. Current treatments for the disease – benznidazole and nifurtimox – were discovered over 50 years ago, must be taken for at least eight weeks, and sometimes have serious and potentially toxic side effects. They also have not been proven effective in people with severe chronic symptoms. There is an urgent need to replenish the drug development pipeline and identify and develop new, safe, and effective oral treatments for all Chagas patients – including women who are pregnant or breastfeeding.

Project objective

The primary objective of this project is to identify novel T. cruzi active series from a unique proprietary compound collection made available by Shionogi & Co., Ltd. (Shionogi).

Project design

A chemically diverse library of approx. 42,000 compounds specifically designed for this project from Shionogi’s chemical library will be screened against the intracellular amastigote stage of T. cruzi at Institute Pasteur Korea in a cell-based, high-throughput screening system. A sequential single concentration followed by full dose-response scheme will be applied. Hit series meeting GHIT/DNDi criteria for potential Chagas disease treatments will be prioritized for further development.

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

Chagas disease was first described over a century ago, yet only two treatments – both with serious and potentially toxic side effects – have ever been developed for this neglected tropical disease, and there are few compounds in the development pipeline. New drugs that can cure Chagas disease and prevent the development of life-threatening complications are urgently needed. We aim to discover novel early hits and lead series with pertinent mechanisms of action that could be developed into safe and effective drugs that can change the treatment paradigm for Chagas disease.

What sort of innovation are you bringing in your project?

A unique and chemically diverse proprietary library of approx. 42,000 compound members has been specifically designed for this project in collaboration with Shionogi to maximize opportunities to identify novel and attractive new scaffolds for further development.

Role and Responsibility of Each Partner

Shionogi will make the compound library physically available to DNDi via its partner screening center, Institute Pasteur Korea, who will be responsible for screening the library. The results will be reviewed by the project partners, with Shionogi undertaking quality control of the hits prioritized for further development.

Others (including references if necessary)

Chatelain, E and Ioset, JR. Expert Opin. Drug Discov. 2018, 13, 1 link Phenotypic screening approaches for Chagas disease drug discovery: Expert Opinion on Drug Discovery: Vol 13, No 2