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mrz
21-08-03, 02:50
Chinese herb reveals vital malaria weakness
18:00 20 August 03
NewScientist.com news service

A hitherto unknown but vital weakness in the malaria parasite has been exposed by studying extracts from ancient Chinese anti-fever remedies. The discovery opens a new front in the fight against the parasite, which has become resistant in most parts of the world to the most common anti-malarial drug, chloroquine.

Derived from the Chinese herb qinghao, or sweet wormwood (Artemisia annua), the extracts have already saved millions of patients in south-east Asia who would otherwise have suffered or died when conventional drugs failed.

Now researchers have discovered how the drugs, called artemisinins, actually work, revealing a chink in the Plasmodium falciparum parasite's armour. The chink is one of the two enzymes that enable the parasite to pump the correct amount of calcium into its cell membranes.

"Artemisinin hits one of those pumps directly," says Sanjeev Krishna of St George's Hospital Medical School in London, UK, the head of the research team. Once the calcium pump is disabled, the parasite dies within hours, although Krishna does not yet know the precise mechanism.


Killing power


The discovery of the enzyme, called Plasmodium falciparum ATP6, or PfATP6, provides a juicy new target for drug makers and for researchers like Krishna who want to improve the killing power of artemisinins.

What is more, the gene that encodes the pump can now be monitored in parasites worldwide to see if it mutates to make the parasite resistant to artemisinins. "We could look for and anticipate resistance, instead of responding when it happens," says Krishna.

The discovery that artimisinins hit the enzyme came as a surprise, because the assumption till now has been that the extracts damage chambers where the parasite digests blood meals.

To prove the enzyme was the key, Krishna's team isolated it by injecting the messenger RNA that codes for PfATP6 into eggs of the frog Xenopus laevis. By comparing the effects of artemisinins with a chemical known to block the enzyme's action, as well as with as drugs such as chloroquine, they were able to show that artemisinins block PfATPt both in the eggs and in intact malarial parasites.


Vulnerable enzyme


Manufactured in China and Vietnam, artemisinins are already having a huge impact in areas of south-east Asia where resistance to other drugs is rife.

Krishna says that the drugs are now beginning to prove their worth in Africa too, and combinations of artemisinins with other drugs are proving most effective. Together with Peter Kremsner of the University of Tubingen in Germany, Krishna's team is testing a combination with amodiaquine on children in Gabon.

Robert Ridley, coordinator of product development for tropical diseases at the World Health Organization in Geneva, says that the discovery should allow new artemisinins to be developed that work in three to four days, rather than the week that current formulations take. This would make it easier to patients to stick to a drug regime, he says.

And the discovery of the vulnerable enzyme should encourage the search for new drugs, which are desperately needed as resistance to older drugs escalates (see graphic).

Journal reference: Nature (vol 424, p 957)


Andy Coghlan

http://www.newscientist.com/news/news.jsp?id=ns99994079

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