The Pharmaceutical Journal
Vol 270 No 7248 p642
10 May 2003

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Nature Structural Biology abstract (more)

Enzyme structure may lead to new anti-malaria drugs

Publication of the structure of an enzyme produced by the malaria parasite may allow the development of new antifolate drugs to which there may be less resistance than there is to existing medicines.

A team of researchers from Bangkok and Edinburgh have determined the structures of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) extracted from drug-resistant wild strains of the malaria parasite.

The enzyme is the target of drugs such as pyrimethamine and proguanil that act by inhibiting the dihydrofolate reductase part. Resistance to these antifolate drugs is known to be caused by mutations in the enzyme.

Unlike in higher animals, the two parts of the enzyme are bound together for greater efficiency of action and it is thought that dihydrofolate (DHF) is rapidly channelled from the TS to the DHFR part. The researchers say that the structure they have found has two positively charged grooves along which DHF might be electrostatically channelled. These channels are linked to the way in which the two parts of the enzyme are joined. They suggest that new families of inhibitors could be developed, targeted at this feature, rather than other active sites. These might then inhibit the enzyme without interfering with similar activity in the host.

The study is published in the May issue of Nature Structural Biology (2003;10:357).