CHINESE herbalists use extracts from the shrub wormwood, Artemisia annua, to treat fever, and the active compound is showing great promise against drug-resistant malaria (In Brief, 23 April 1994). Now chemists in the US say they know why. The discovery of how this compound, called artemisinin, kills the malaria parasite could lead to a series of new antimalarial drugs.
Across large parts of the tropics, alkaloid drugs such as chloroquine and quinine are becoming less and less effective against Plasmodium falciparum, the organism that causes malaria. So far, the parasite has not evolved resistance to artemisinin, but the drug is difficult to synthesise, so chemists would like to find simpler drugs with similar effects. This should be easier, thanks to the work of a team led by Gary Posner of Johns Hopkins University in Baltimore.
Artemisinin molecules contain a highly reactive peroxide group 鈥� two linked oxygen atoms 鈥� sitting close to a third atom of oxygen. Researchers knew that this 鈥渢rioxane鈥� group can damage biological molecules. But Posner and his colleagues Jared Cumming, Poonsakdi Ploypradith and Chang Ho Oh believe they know why artemisinin inflicts particularly severe damage on P. falciparum cells.
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It turns out that the parasite is its own worst enemy. P. falciparum hitches a ride in its human host鈥檚 bloodstream and makes full of use of this rich source of iron. 鈥淭he malaria parasites get their iron by digesting the host鈥檚 haemoglobin,鈥� explains Posner. This iron is stored inside the cells of the parasite. But iron can chemically reduce molecules containing oxygen, and this is the parasite鈥檚 downfall. When the molecule is artemisinin, Posner鈥檚 team found that the reaction releases a deadly byproduct containing iron in a highly reactive Fe(IV) state linked to an oxygen atom (Journal of the American Chemical Society, vol 117, p 5885). Fortunately, it seems that the host鈥檚 red blood cells are not so susceptible to the drug: when exposed to artemisinin, the iron in these cells鈥� haemoglobin yields less of the Fe(IV) compound.
The Fe(IV) byproduct, the researchers say, races round P. falciparum cells, smashing into biomolecules and sending them down a chain reaction to destruction. Posner believes it should be possible to design simpler compounds containing trioxane groups which would also yield the Fe(IV) compound when reduced by iron. 鈥淭hese would operate by the same molecular mechanism but be much less expensive and easier to prepare,鈥� he says.
The researchers have also found that the drug is converted into a compound that disrupts the parasite鈥檚 DNA by adding alkyl organic groups to it. This means that it cannot copy its DNA, and so is unable to reproduce. Posner says his team and other scientists are trying to modify artemisinin to enhance this second effect (see Diagram).
