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Anti-Parasitic Drug Discovery in Epigenetics

Anti-Parasitic Drug Discovery in Epigenetics

Objective

This proposal builds on the proven methodology developed in the SEtTReND FP7 project to develop inhibitors of schistosome HME as lead compounds for new drugs. We will employ a target-based strategy for the development of novel drug leads against schistosomiasis, leishmaniasis, Chagas disease and malaria by targeting histone modifying enzymes (HME), in particular those involved in acetylation/deacetylation and methylation/demethylation. The principal objectives of A-PARADDISE are:
- The identification of HMEs from Leishmania sp. and Trypanosoma cruzi and the molecular characterization and functional characterization of selected potential targets,
- Phenotypic screening of Leishmania, T. cruzi, S. mansoni and P. falciparum using HME class inhibitors, inhibitors developed specifically against S. mansoni and P. falciparum HMEs. This will permit us to obtain a comprehensive view of inhibitor classes and chemical scaffolds of interest,
- Production of recombinant Leishmania and T. cruzi HME proteins, structural studies. Selected, validated target enzymes will be produced, crystallized and analysed by X-ray diffraction. Assays will be optimized to permit testing of inhibitors,
- High-throughput and structure-based (in silico) screening of selected HMEs. Inhibitors selected will be further screened by phenotypic assays on the parasites in vitro,
- Optimisation of inhibitor structures by chemical synthesis based on molecular modelling studies (inhibitors of all origins),
- Transcriptomic analysis of drug-treated parasites to verify target specificity and mechanism of action (all parasites),
- Pharmacological and toxicological studies (in vitro and in vivo) of selected inhibitors, in vivo testing of compounds in parasite-infected mice.
The overall objective of the A-PARADDISE project is to develop optimized epigenetic inhibitors for further testing and optimisation as drug candidates against the four parasites studied.

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Address

Rue De Tolbiac 101
75654 Paris

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 755 604

Administrative Contact

Virginie Chameroy (Mrs.)

Participants (15)

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CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE

France

EU Contribution

€ 440 840

MARTIN-LUTHER-UNIVERSITAET HALLE-WITTENBERG

Germany

EU Contribution

€ 229 800

UNIVERSIDADE FEDERAL DO RIO DE JANEIRO

Brazil

EU Contribution

€ 285 474

UNIVERSIDADE DE SAO PAULO

Brazil

EU Contribution

€ 411 665

ALBERT-LUDWIGS-UNIVERSITAET FREIBURG

Germany

EU Contribution

€ 374 400

FUNDACAO OSWALDO CRUZ

Brazil

EU Contribution

€ 866 520

INSERM TRANSFERT SA

France

EU Contribution

€ 313 190

KANCERA AB

Sweden

EU Contribution

€ 952 100

ADLEGO BIOMEDICAL AB

Sweden

EU Contribution

€ 184 863

GRIFFITH UNIVERSITY

Australia

THE UNIVERSITY OF QUEENSLAND

Australia

UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA

Italy

EU Contribution

€ 284 016

UNIVERSITY OF EAST ANGLIA

United Kingdom

EU Contribution

€ 334 241

Universidade Federal de Viçosa

Brazil

EU Contribution

€ 268 680

INSTITUT PASTEUR

France

EU Contribution

€ 298 598

Project information

Grant agreement ID: 602080

Status

Closed project

  • Start date

    1 February 2014

  • End date

    31 January 2017

Funded under:

FP7-HEALTH

  • Overall budget:

    € 8 638 614

  • EU contribution

    € 5 999 991

Coordinated by:

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France