January 12, 1996
Researchers Identify New Target for Malaria Drug Development
Deducing the role of a crucial protein, researchers have
discovered one of the malaria parasite's top survival strategies.
Their findings could lead to desperately needed drugs against the
disease.
Daniel E. Goldberg
of HHMI at Washington University
School of Medicine in St. Louis and colleagues have figured out
how the malaria parasite,
Plasmodium
, transforms the
potentially lethal remains of its food into harmless solid waste.
“There is an urgent need for new drugs now that vast areas of the world have substantial chloroquine resistance.”
Daniel E. Goldberg
Living inside red blood cells, the malaria parasite feeds on
the oxygen-carrying pigment hemoglobin. But like a gourmet who
dines on puffer fish--a delicacy that can prove poisonous--
Plasmodium
must be careful to avoid being killed by heme, a
toxic byproduct of hemoglobin digestion.
"So
Plasmodium
ingests hemoglobin and deposits it into a
digestive vacuole," Goldberg explained. "The heme that pops out
is polymerized into a non-toxic crystalline lattice called hemozoin,
and the parasite then feeds on the globin."
Publishing in the January 12 issue of the journal
Science
,
Goldberg, David J. Sullivan, Jr., an HHMI associate and
postdoctoral fellow at Washington University, and research
associate Ilya Y. Gluzman showed that an enzyme called
histidine-rich protein II (HRP II) catalyzes this heme
polymerization.
In the lab, the researchers first demonstrated HRP II's
presence in the malaria parasite's digestive vacuole. They then
incubated HRP II in test tubes filled with heme. HRP II
readily converted the toxic heme to harmless, sludgy hemozoin.
Now that heme detoxification is understood, researchers can
learn more about how top antimalarial drugs like chloroquine
work. The team found that chloroquine
inhibits HRP-mediated polymerization, leaving free-floating heme
to kill the malaria parasite.
Scientists may now be able to modify chloroquine or design
other drugs to block heme's breakdown. "There is an urgent need
for new drugs now that vast areas of the world have substantial
chloroquine resistance," Goldberg noted.
The World Health Organization estimates that 300
million people are infected by the malaria parasite. Malaria kills
more than 1 million people--mostly children--every year.
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