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 helped millions of patients in south-east Asia who would otherwise have suffered or died when conventional drugs failed (New 杏吧原创, 13 July 1996, p 4). Now researchers have discovered how the drugs, called artemisinins, actually work, revealing a chink in the Plasmodium falciparum parasite鈥檚 armour.
The chink is one of the two enzymes that enable the parasite to pump the correct amount of calcium into its cell membranes. 鈥淎rtemisinin hits one of those pumps directly,鈥� says Sanjeev Krishna of St George鈥檚 Hospital Medical School in London, the head of the research team. Once the calcium pump has been disabled, the parasite dies within hours, although Krishna doesn鈥檛 yet know the precise mechanism.
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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. 鈥淲e could look for and anticipate resistance, instead of responding when it happens,鈥� says Krishna.
The discovery that artemisinins 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鈥檚 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鈥檚 action, as well as with drugs such as chloroquine, they were able to show that artemisinins block PfATP6 both in the eggs and in intact malarial parasites (Nature, vol 424, p 957).
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 and other drugs are proving most effective. Together with Peter Kremsner of the University of T眉bingen in Germany, Krishna鈥檚 team is testing a combination of artemisinins and 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 3 to 4 days, rather than the week that current formulations take. This would make it easier for 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).
