Exploitation of targets for chemotherapy in the polymine metabolism of filarial worms

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

• 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

Programme(s)

• FP3-STD 3 - Specific research and technological development programme (EEC) in the field of the life sciences and technologies for developing countries, 1990-1994

Topic(s)

Data not available

Call for proposal

Data not available

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Bernhard Nocht Institut für Schiffs- und Tropenkrankheiten

Address

Bernhard-nocht-straße 74
20359 Hamburg
Germany

Participants (2)

London School of Hygiene and Tropical Medicine

United Kingdom

Address

Keppel Street
WC1E 7HT London

Université Nationale de Bénin

Nigeria

Address

Benin