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Dihydrofolate reductase-thymidylate synthase from plasmodium vivax and p. falciparum as targets for antimalarial chemotherapy.

Objective

Both dihydrofolate reductase-thymidylate synthase (DHR-TS) and DHFR from P. vivax will be cloned and expressed from E.coli. The kinetic properties of the expressed enzyme and the profiles of inhibition by various antifolates will be studied, in order to find out whether it is inherently resistant to inhibition. Mutants of P.vivax DHFR, both found in the field and artificially designed, as well as mutants of P.falciparum will be made and studied. The results will be used to model the three-dimensional structure of the enzymes, especially around the active site. Both DHFR and DHFR-TS from the two sources will be prepared in sufficient amounts for crystallization and structure determination by X-ray diffraction. Newly designed antifolates and those synthesized previously will be tested for their inhibitory activities. The mode of binding of such agents to the enzyme will be studied both from modelling and X-ray studies. Such agents will be important as leads to new antifolate drugs against both types of malaria. Agents with activity against both P. vivax and P.falciparum DHFR will be of special interest, in view of the common occurrence of mixed infections.

Topic(s)

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Call for proposal

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Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
EU contribution
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Address
South Parks Road
OX1 3QY OXFORD
United Kingdom

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Participants (3)