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Schistosoma Epigenetics - Targets, Regulation, New Drugs

Objective

We propose to develop novel drug leads for the therapy of the major human parasitic disease, schistosomiasis, using a holistic approach that will enable us to progress from the cloned target protein to the lead compound and from epigenetic inhibitors to crucial targets. For this, we have chosen to target the histone modifying enzymes (HME); histone deacetylases (HDAC), histone acetyltransferases (HAT), histone methyltransferases (HMT) and histone demethylases (HDM) of Schistosoma mansoni. In the course of the project the members of HDAC classes I, II and III (sirtuins) HAT, HMT and HDM encoded in the genome will be identified. In parallel, a reverse chemical genetics approach using generic inhibitors of HME subclasses available within the consortium in cultures of schistosome larvae will identify those classes that are bona fide drug targets. These enzymes will be validated as therapeutic targets individually or collectively using RNAi to invalidate the corresponding genes. Potential inhibitors (HDACi, HATi, HMTi, HDMi) will be screened by in silico docking to the modelled catalytic domains of the enzymes and collections of analogues will be tested for their ability to inhibit the activity of the corresponding recombinant proteins in high-throughput assays. We will also establish gene expression profiles corresponding to HME invalidation (by RNAi) and inhibition (using drug candidates in cultured larval stages (schistosomula) that will enable the determination of the specificity of action of the drugs. Finally, in vivo testing of the best candidates will be done in infected mice. In this way, during the study period we aim to develop a series of candidate molecules that can progress to clinical trials.

Field of science

  • /natural sciences/biological sciences/genetics and heredity
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-HEALTH-2009-single-stage
See other projects for this call

Funding Scheme

CP-FP-SICA - Small/medium-scale focused research project for specific cooperation actions dedicated to international cooperation partner countries(SICA)

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Address
Rue De Tolbiac 101
75654 Paris
France
Activity type
Research Organisations
EU contribution
€ 623 400
Administrative Contact
Rofigua Hakem (Ms.)

Participants (8)

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
France
EU contribution
€ 350 916
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
Activity type
Research Organisations
Administrative Contact
Steve Brooks (Dr.)
MARTIN-LUTHER-UNIVERSITAET HALLE-WITTENBERG
Germany
EU contribution
€ 245 028
Address
Universitaetsplatz 10
6108 Halle (Saale)
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Sigrid Köhne (Dr.)
UNIVERSIDADE FEDERAL DO RIO DE JANEIRO
Brazil
EU contribution
€ 261 378
Address
Av Brigadeiro Trompowski Sn 2
21941 590 Rio De Janeiro
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Maria Helena Lacorte (Prof.)
ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Germany
EU contribution
€ 350 995
Address
Fahnenbergplatz
79098 Freiburg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Manfred Jung (Prof.)
FUNDACAO OSWALDO CRUZ
Brazil
EU contribution
€ 385 296
Address
Avenida Brasil 4365
21040 900 Rio De Janeiro
Activity type
Research Organisations
Administrative Contact
Guilherme Oliveira (Dr.)
INSERM TRANSFERT SA
France
EU contribution
€ 54 705
Address
Rue Watt 7
75013 Paris
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Louis Jammayrac (Mr.)
INOVACIA AB
Sweden
EU contribution
€ 603 900
Address
Banvaktsvagen Karolinska Institutet Science Park 22
171 48 Solna
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Johan Schultz (Dr.)
UNIVERSIDADE DE SAO PAULO
Brazil
EU contribution
€ 424 380
Address
Rua Da Reitoria 109 Butanta
05508 900 Sao Paulo Sp
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Hans Viertler (Prof.)