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Gary Posner, Scowe Professor of
Chemistry at Johns Hopkins and leader of a team that has developed
a new series of malaria drugs.
Photo by Will Kirk/JHU |
An article about the team's work is slated to
appeared on the Web on April 17 (2007) 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,
mostly children and mostly in developing nations. The parasite that
causes the disease is spread by female mosquitoes feeding on human
blood. The most commonly 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 Johns Hopkins 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 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.
But the first generation of trioxane drugs also 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 believe that their new compounds
address those disadvantages.
"Our semi-synthetic artemisinin-derived compounds
successfully overcome the disadvantages of their first-generation
predecessors," he 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. 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." |
