Plant-Derived Ancient Chinese Folk Remedy Cures Malaria

Scientists have cured malaria-infected mice with single shots of a new series of potent, long lasting synthetic drugs modeled on an ancient Chinese herbal folk remedy.

The team also has developed several other compounds that defeated the febrile disease in rodents after three oral doses. The peroxide compounds, containing a crucial oxygen-oxygen unit, promise not only to be more effective than today's best malaria remedies, but also potentially safer and more efficient.

Since 1992, Prof. Gary Posner and his John Hopkins School of Medicine (Baltimore, MD, USA) team, including collaborator Theresa Shapiro, have been tackling that challenge by designing a series of peroxide compounds, called trioxanes. As a class, these compounds have proven to be unusually valuable in several ways, from their brisk and potent antimalarial activity to their lack of resistance and cross-resistance with other antimalarial agents, Prof. Shapiro said.

The Johns Hopkins trioxanes mimic artemisinin, the active agent in a Chinese herbal drug used to treat malaria and other fevers for thousands of years. Artemisinin comes from the Artemisia annua plant, an herb also known by a variety of names including sweet wormwood.

The oxygen-oxygen unit in the peroxides causes malaria parasites essentially to self-destruct. The parasites digest hemoglobin, the oxygen-carrying pigment of red blood cells, and in the process, release a substance called heme, a deep-red iron-containing blood pigment. When the heme encounters peroxides, a powerful chemical reaction occurs, releasing carbon-free radicals and oxidizing agents that eventually kill the parasites.

Our semi-synthetic artemisinin-derived compounds successfully overcome the disadvantages of their first-generation predecessors, Prof. Posner said. Most important is their curative activity after a single, low dose, which is distinctly unusual. But based on our intentional design, they may also have a longer half-life in animals. We also designed them to be more lipophilic, meaning they have an enhanced ability to dissolve in fats and thus to arrive inside malaria-infected red blood cells. In addition, the new compounds are far less likely to break down into toxic substances when they are metabolized in the test animals' bodies, making them potentially safer than their predecessors.

Although the substance is inexpensive by Western standards, the widespread use of artemisinins in the developing world remains limited, in part by availability and the cost of separating the active ingredient from the Artemisia annua plant. Prof. Posner and his team said that the potency and curative activity of their compounds provide a substantially more efficient and economical use of the price-setting natural product.

An article about the team's work appeared online in the April 17, 2007, edition of The Journal of Medicinal Chemistry.


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