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Project title


PVPFDHFR

MALARIA

Dihydrofolate Reductase-Thymidylate Synthase from Plasmodium Vivax and P. falciparum as Targets for Antimalarial Chemotherapy
Framework programme:
5
Project number:
ICA4-CT-2001-10077
EC contribution:
€ 589 995
Duration:
36 months
Type:
RS
Starting date:
1 November 2001

Summary:

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 crystallisation and structure determination by X-ray diffraction. Newly designed antifolates and those synthesised previously will be tested for their inhibitory activities. The mode of binding of such agents to the enzyme will be studied from both 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.

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