Objective
Safe and potent drugs for the treatment of onchocerciasis and lymphatic filariasis are urgently needed but are presently not available. The aim of the proposed research project is the identification of targets for chemotherapy in the polyamine metabolism of filarial worms. In previous studies within the STD2 programme evidence was provided that filarial parasites are more susceptible to elevated polyamine levels than the host organism. In addition, it was shown that in filarial worms contrary to the mammalian host the polyamine oxidase is the rate-limiting step in the degradation of excessive polyamines and that the nematode enzyme is clearly different from the mammalian counterpart by substrate and inhibitor specificity. Based on these results a strategy for chemotherapy is proposed which will exploit the outstanding susceptibility of the parasites towards elevated polyamine levels. A mechanism-based inhibitor for the parasite polyamine oxidase has been identified and used as a chemical lead to demonstrate the efficacy of the biochemical target. The in vitro treatment of worms maintained in medium resulted in accumulation of polyamines and death of worms. Other mechanisms involved in the regulation of polyamine concentrations like down-regulation of polyamine uptake, acetylation of polyamines followed by secretion as well as sequestration of polyamines by binding to peptides will be investigated to exclude that the parasite escapes from the polyamine stress caused by the inhibition of the polyamine oxidase. Attempts will be made to improve the potency of the class of already identified mechanism-based inhibitors. In a more rational approach of drug design the three-dimensional structure of the enzyme will be determined by X-ray crystallography for the design of enzyme inhibitors with selectivity for the parasite polyamine oxidase. Due to paucity of biological material available from'onchocerca volvulus this approach will depend on the production of recombinant enzyme protein for the growth of crystals. The proposed research project will be an approach for the rational design of urgently needed drugs against filarial infections. It will also strengthen the cooperation of European institutions involved in research on tropical diseases and will provide training for Young scientists from Nigeria and thereby contribute to the transfer of technoloqy to developing countries.
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.
- medical and health sciences health sciences tropical medicine
- medical and health sciences basic medicine medicinal chemistry
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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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 (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
20359 Hamburg
Germany
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.