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In light of a surprising new result, scientists are reconsidering how the antimalarial drug artemisinin might kill microbial parasites that cause malaria. Instead of overwhelming the parasites with nonspecific radical damage, artemisinin has now been shown to target a critical calcium-pumping enzyme [Nature, 424, 957 (2003)]. ON TARGET The identification of a biological target for artemisinin by Krishna and Eckstein-Ludwig (shown) may lead to new therapies and ease tracking of emerging resistance. ACADEMIC SERVICES/ST. GEORGE'S HOSPITAL MEDICAL SCHOOL PHOTO With resistance to the most commonly used antimalarial drugs on the rise, artemisinin--the active ingredient of a traditional Chinese herbal remedy for malaria--is becoming increasingly important. The drug and its derivatives are potent, specific, and nontoxic, but they must be administered often because they're quickly degraded in the bloodstream. An international team led by postdoc Ursula Eckstein-Ludwig and professor Sanjeev Krishna of St. George's Hospital Medical School, in London, has now identified a molecular target for artemisinin. With a target in hand, "the design of new artemisinin derivatives can proceed in a truly rational manner," comments chemistry professor Richard K. Haynes of Hong Kong University of Science & Technology. The identification of a target may also help scientists to track emerging resistance to these drugs. Artemisinin contains a reactive endoperoxide bridge that can be cleaved by ferrous iron, generating highly reactive carbon-centered radicals. The leading theory held that the drug makes its way to the parasite's food vacuole, where hemoglobin from the human host's red blood cells is catabolized. In the vacuole, artemisinin was thought to interact with Fe2+-heme, setting off a "dirty bomb" of artemisinin-derived radicals that would damage nearby biomolecules and eventually kill the parasite. Eckstein-Ludwig and Krishna's work, however, suggests that the drug acts more specifically, by irreversibly inhibiting a critical parasite enzyme. This enzyme, called PfATP6, uses the energy generated from cleaving adenosine triphosphate to pump calcium into membrane organelles. Noting that artemisinin shares a sesquiterpene backbone with thapsigargin, an inhibitor of PfATP6 and its human relatives, Eckstein-Ludwig and Krishna decided to test whether artemisinin might target PfATP6, too. They expressed the enzyme in frog eggs and found that artemisinin does indeed inhibit the parasitic enzyme (although not its human counterpart). Krishna believes that artemisinin must be activated by iron in order to inhibit PfATP6. Two pieces of evidence support this hypothesis, he says. First, an artemisinin derivative lacking the endoperoxide bridge can't inhibit PfATP6. And second, a reagent that sequesters free iron prevents artemisinin from inhibiting PfATP6. Still, "a lot of questions remain to be answered," Krishna says. For instance, it remains to be seen what iron species might activate artemisinin, what the structure of this activated species might be, or how the activated drug might bind to PfATP6. It's also possible that PfATP6 is not artemisinin's only biological target. Krishna and his colleagues are now trying to model how artemisinin might bind to PfATP6, using a recently published structure of thapsigargin bound to the mammalian version of the enzyme as a guide. This could lead to the design of longer lasting artemisinin derivatives, he says. |
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