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Discovery and Screening activities

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Target diseases: HAT, VL, and Chagas
Partners: DNDi is engaged in a number of exploratory activities with partners, including: Anacor, USA; Eskitis (Griffith University), Australia; Federal University of Ouro Preto, Brazil; Fiocruz, Brazil; Institut Pasteur Korea (IPK), South Korea; Institut de Recherche pour le Développement (IRD), France; GlaxoSmithKline (GSK), Spain; London School of Hygiene & Tropical Medicine (LSHTM), UK; Merck, Canada & USA; Murdoch University, Australia; Swiss Tropical and Public Health Institute, Switzerland (Swiss TPH); TI Pharma, the Netherlands; University of Antwerp, Belgium; University of Dundee, UK; Pfizer, NITD, TB Alliance,  among others
DNDi project managers: Jean-Robert Ioset (early-stage discovery and screening), Rob Don (HAT), Denis Martin (VL), and Eric Chatelain (Chagas)
Funding: Médecins Sans Frontières/Doctors without Borders, International; Spanish Agency for International Development Cooperation (AECID), Spain; Department for International Development (DFID), UK; Ministry of Foreign and European Affairs (MAEE), France; GTZ on behalf of the Government of the Federal Republic of Germany, Germany; individual donors.

SOURCING


DNDi’s Discovery strategy includes a variety of approaches in terms of compound sourcing:

Compound mining
Proactive investigation of compound series on which no or limited biological data existed and compounds were collected from various investigators. An example of this approach is our compound mining effort undertaken in 2005 to explore new and old nitroimidazoles as drug leads against human African trypanosomiasis (HAT). Over 500 compounds from 15 different sources were identified, accessed, and tested.  

Mining for promising chemical classes
Identification of promising chemical classes as source for lead compounds. From libraries of collaborating pharmaceutical and biotech companies, promising compound classes can be identified by sampling a subset of representative compounds and test them for antiparasitic activities. Usually, hundreds of analogs and the associated biological data are already available from the partners who provide their collections. Subsequent optimisation from the selected classes would be more efficient as the result of existing know-how. Examples of interesting classes include pyridones and protease inhibitors (GlaxoSmithKline GSK), cruzipain inhibitors (Merck), oxaboroles (Anacor Pharmaceuticals), licochalcones, and others (e.g., macrolides, PDE inhibitors, etc.).

Chemical diversity

Access to diversity sets/libraries from various institutions and pharmaceutical companies (natural products, synthetic compounds).

Target-based
Screening compounds and assessing their activity against a specific target, known to be essential for parasite growth, e.g., Drug Discovery Unit at the University of Dundee, UK (VL); TI Pharma consortium (HAT, VL).


SCREENING

HTS
High throughput screening (HTS) of large-size libraries for Leishmania and T. cruzi (Institut Pasteur Korea), and T. b. brucei (Eskitis) have been developed and are used to identify novel hit compounds.


Reference Screening Centres

The London School of Hygiene and Tropical Medicine (LSHTM), the Swiss Tropical and Public Health Institute (Swiss TPH), and the University of Antwerp serve as reference screening centres to ensure that screening methodologies are comparable, and that in vitro and in vivo assays at different sites and with different groups meet the same standard. The centres also provide expert parasitology advices that ensures the quality of our data and work.


Last update: March 2010


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