Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
Aufforderung zur Vorschlagseinreichung
FP7-HEALTH-2013-INNOVATION-1
Andere Projekte für diesen Aufruf anzeigen
Finanzierungsplan
CP-FP - Small or medium-scale focused research projectKoordinator
75654 Paris
Frankreich
Auf der Karte ansehen
Beteiligte (15)
67404 Illkirch Graffenstaden
Auf der Karte ansehen
6108 Halle
Auf der Karte ansehen
21941 590 Rio De Janeiro
Auf der Karte ansehen
05508 900 Sao Paulo Sp
Auf der Karte ansehen
79098 Freiburg
Auf der Karte ansehen
21040 900 Rio De Janeiro
Auf der Karte ansehen
75015 PARIS
Auf der Karte ansehen
171 48 Solna
Auf der Karte ansehen
751 03 Uppsala
Auf der Karte ansehen
4111 Brisbane
Auf der Karte ansehen
4072 Brisbane
Auf der Karte ansehen
00185 Roma
Auf der Karte ansehen
NR4 7TJ Norwich
Auf der Karte ansehen
36570-000 Viçosa
Auf der Karte ansehen
75724 Paris
Auf der Karte ansehen