Introduction and Background of the Project

Introduction

There is an urgent need for new treatments for Chagas disease. Existing medications lack effectiveness against chronic infection, require long regimens, and have several adverse effects. Given their integral roles in trypanosome signalling and low homology with human counterparts, phosphodiesterases (PDEs) have been posited as drug targets for Chagas disease. Given the lack of identified targets and critical need for new mechanism-of-action drugs, these enzymes merit identification and development of inhibitors.

Project objective

We propose to conduct a hit-to-lead campaign of phosphodiesterase (PDE) inhibitors for Chagas disease. We will leverage findings from a previous GHIT-funded project for the generation of structure-activity relationship (SAR) data to advance a medicinal chemistry campaign. We aim to identify compounds with favourable profiles and in vivo efficacy using an acute model of Chagas disease. This work represents a crucial contribution to the drug discovery pipeline as the endpoint for this proposal is the identification of leads that are primed for further optimization, bringing us closer to delivering an urgently needed, novel mechanism-of-action drug candidate for Chagas disease.

Project design

New compounds will be subjected to iterative cycles of design, synthesis, and profiling in in vitro potency, selectivity, and DMPK assays, followed by in vivo PK studies. Structure-activity and structure-property relationships gleaned from these activities will be used to continually refine our analog design hypotheses. Potent analogs with acceptable in vitro and in vivo profiles will be progressed for in vivo efficacy testing using the Chagas acute model.

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

There is an urgent need for development of new treatments for Chagas disease, which affects approximately 7 million people. The two currently approved medications, benznidazole and nifurtimox, were discovered over fifty years ago. These medications require long treatment courses (60-90 days) and cause adverse effects that often result in treatment discontinuation. Furthermore, they lack effectiveness against chronic infection, which is responsible for the majority of morbidity and mortality in Chagas disease. There is a paucity of new drugs under development and in clinical trials.

This project seeks to address this pressing need by efficiently developing new compounds with the potential to achieve the target product profile for a new Chagas disease drug: a short, oral, well-tolerated treatment that is effective against chronic infection.

What sort of innovation are you bringing in your project?

There is a lack of validated drug targets for Chagas disease, and it is essential to add new drug candidates from novel chemical classes to the pre-clinical pipeline that act via novel and pertinent mechanisms of action. New candidates will maximize the chances of successfully completing the development of a safe and efficacious new drug that could be used in a short-course, oral treatment against the chronic stage of the disease. The innovation of this collaborative project is to optimize new hits according to DNDi-recommended lead criteria for Chagas disease and add new leads to the early-stage pipeline of projects that are chemically novel, that inhibit a novel and fairly unexplored target in T. cruzi, and that can progress to the lead optimization.

Role and Responsibility of Each Partner

Eisai will be the project lead and responsible for overall management. Eisai team members will be part of the medicinal chemistry design team and provide DMPK and safety expertise for evaluation of candidates.

DNDi team members will serve as members of the medicinal chemistry design team and will oversee efforts from their scientific network for in vitro biology, efficacy assays in the acute model, and target engagement studies.

At Universidad Nacional de la Plata (UNLP), Dr. Talevi’s group will serve as members of the medicinal chemistry design team.

At Fundación INGEBI, Dr. Alonso’s laboratory will conduct biochemical screening and activity assays against whole-cell T. cruzi parasites. His group will also provide expertise in trypanosome PDE biology.

At Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), Dr. Alba Soto will profile promising compounds against alternate forms and strains of the parasite and as manage studies in Chagas models.

DNDi, UNLP, INGEBI, and IMPaM will also contribute their experience as investigators in countries where Chagas disease is endemic.