Johns Hopkins University researchers 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.
These 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, said research team leader Gary
Posner, Scowe Professor of Chemistry in the
Krieger School of Arts and Sciences.
An article about the team's work appeared on the Web
April 17 in the ASAP section of the Journal of Medicinal
Chemistry.
"We are disclosing, for the first time, the curative
activity of a new generation of compounds that are
long-lasting and therapeutic, even when used by
themselves," Posner said. "Older drugs in this family of
peroxide antimalarials also are known to be fast-acting,
but they are unfortunately short-lived and not curative
when used by themselves."
Though they say their results are very promising, the
researchers caution that the new compounds must be
thoroughly tested for safety and for how they are absorbed,
distributed and metabolized in, and eliminated from,
rodents' bodies before human tests begin.
Malaria afflicts between 300 million and 500 million
people a year, killing between 1.5 million and 3 million,
most of them children in developing nations. The parasite
that causes the disease is spread by female mosquitoes
feeding on human blood. The most common fatal species of
the malaria parasite now shows strong resistance to most
current treatments, making the development of effective new
drugs a worldwide priority.
Since 1992, Posner and his team, which includes
collaborator Theresa Shapiro, professor and chair of Clinical
Pharmacology at the School of Medicine, 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,"
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 other names, including sweet wormwood.
The oxygen-oxygen unit in the peroxides essentially
causes malaria parasites 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.
The first generation of trioxane drugs had a number of
shortcomings, including a half-life of less than one hour.
(A drug's half-life is the amount of time it takes for half
of it to be metabolized.) Posner and team said they believe
that their new compounds address those disadvantages.
"Our semisynthetic artemisinin-derived compounds
successfully overcome the disadvantages of their
first-generation predecessors," 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 artemisinins are inexpensive by Western
standards, their widespread use in the developing world
remains limited, in part by availability and the cost of
separating the active ingredient from the Artemisia annua
plant. Posner and his team contend that the potency and
curative activity of their compounds provide "a
substantially more efficient and economical use of the
price-setting natural product."
The team's research was supported by the National
Institutes of Health and the Bloomberg School of
Public Health Malaria Research Institute.
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