Anti-parasitic drug discovery in epigenetics

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Project Title: Anti-parasitic drug discovery in epigenetics
Project Number: CORDIS-109335
Project web address: Follow on CORDIS
Organization: Institut National De La Sante Et De La Recherche Medicale, France, Paris
Collaborators: University Of East Anglia, GB
University Of Queensland, AU
Albert Ludwig University Of Freiburg, DE
Griffith University, AU
Fundacao Oswaldo Cruz, BR
Institut Pasteur, FR
Università Degli Studi Di Roma 'La Sapienza', IT
Universidade De São Paulo, BR
Universidade Federal Do Rio De Janeiro, BR
Universidade Federal De Viçosa, BR
Centre Europeen De Recherche En Biologie Et Medecine, FR
Inserm-Transfert Sa, FR
Adlego Biomedical Ab, SE
Kancera Ab, SE
Principal Investigators (PI): Steve Brooks, FR
Louis Jammayrac, FR
Marie-Laure Rosso, FR
Sigrid Köhne, DE
Manfred Jung, DE
Cinzia Murdocca, IT
Virginie Chameroy, FR
Nicki Church, AU
Urban Höglund, SE
Yvonne Kirkham, GB
Daniel Marçal De Queiroz, BR
Marcello Fantappie, BR
Maurício Zuma, BR
Kem Yoshida, BR
Martin Norin, SE
Lyn Fairlie, AU
 
Project Description:
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.
 
Project Terms:
life sciences