Objective
* to develop novel compounds active against human trypanosomiases and leishmaniasis;
* to take advantage of an essential metabolism in these trypanosomatidae that glycolysis represents;
* to design irreversible and quasi-irreversible inhibitors of glycolytic enzymes based on differences between parasites and mammalian enzymes and to import them into the cell either via passive diffusion or via the glucose THT1 transporter.
Expected Outcome
The study will develop compounds capable of specifically blocking glycolysis and therefore limiting the survival of trypanosomes. The work will lead to an improved knowledge of the glycolytic enzymes and transport systems in trypanosomes and leishmania.
The first set of irreversible GAPDH inhibitors will be extended to structures directed towards Arg 231 and the compounds will be transformed into the corresponding prodrugs. Cocrystallisation experiments of these compounds with the enzyme GAPDH from Trypanosoma brucei will be made for the design of improved structures after corresponding modelling.
A parallel work will be made on the T.brucei aldolase enzyme, starting from active structures already identified. In both cases the residue responsible for the formation of the covalent bond will be identified using mutants for the most likely locations.
All the compounds will be assayed for their transport by the glucose transporter THT1 and also on Trypanosome cytosolic esterases which are expected to transform prodrugs into drugs within the cell. Compounds of natural origin will be also studied within the program.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
31062 Toulouse
France
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.