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[afro-nets] Deadly malaria parasite's Achilles heel

Finding deadly malaria parasite's Achilles heel
08 Nov 2005

by Rex Graham
University of California - San Diego

The most deadly malaria parasite has protein 'wiring' that dif-
fers markedly from the cellular circuitry of other higher organ-
isms, a finding which could lead to the development of antima-
larial drugs that exploit that difference.

Researchers at UCSD have discovered that the single-cell para-
site responsible for an estimated 1 million deaths per year
worldwide from malaria has protein "wiring" that differs mark-
edly from the cellular circuitry of other higher organisms, a
finding which could lead to the development of antimalarial
drugs that exploit that difference.

The scientists will report in the Nov. 3 issue of Nature a com-
parison of newly discovered protein-interactions in Plasmodium
falciparum with protein interactions reported earlier in four
other well studied model organisms -- yeast, a nematode worm,
the fruit fly, and a bacterium that causes digestive-tract ul-
cers in humans. The authors of the study, Trey Ideker, a profes-
sor of bioengineering at UCSD's Jacobs School of Engineering,
and two graduate students, Silpa Suthram and Taylor Sittler,
said the malaria parasite's protein interactions "set it apart
from other species."

"We've known since the Plasmodium genome was sequenced three
years ago that 40 percent of its 5,300 proteins are signifi-
cantly similar, or homologous, to proteins in other eukaryotes,
but until now we didn't know that the malaria parasite assembles
those proteins so uniquely," said Ideker. "Since our earlier re-
search showed that yeast, worm, and fly have hundreds of both
conserved proteins and protein interactions, we didn't initially
believe our own analysis, which showed that there are only three
Plasmodium protein interactions in common with yeast and none in
common with the other species studied." The World Health Organi-
zation warns that malaria is a growing threat to health world-
wide, particularly in poor countries. No malaria vaccine has
been developed, and once powerful antimalarial drugs are less
and less effective because Plasmodium falciparum has developed
resistance to those drugs. Even mosquitoes that transmit malaria
are developing resistance to the most commonly used insecti-

"The demonstration that the Plasmodium protein network differs
significantly from those of several model organisms is an in-
triguing result that could lead to the identification of novel
drug targets for fighting malaria," said John Whitmarsh, acting
director of the Center for Bioinformatics and Computational Bi-
ology at the National Institute of General Medical Sciences,
which partially funded the work. "Ideker and his team have dem-
onstrated the effectiveness of a computational approach based on
mathematics for understanding complex biological interactions."

Researchers studying protein expression under controlled labora-
tory conditions have been slowed because techniques designed for
other organisms work poorly with Plasmodium because 80 percent
of its genome is comprised of only two of the four building
blocks of DNA.

Stanly Fields, a professor of genomic sciences at the University
of Washington who invented an ingenious way to identify pairs of
proteins that physically interact with one another, modified his
technique and added special culture conditions to enable his
group to study Plasmodium. Fields's team and collaborators at
Prolexys Pharmaceuticals of Salt Lake City, UT, discovered 2,846
interactions involving 1,312 Plasmodium falciparum proteins. The
team provided data on those interactions to Ideker's group ear-
lier and also reported the results in the Nov. 3 issue of Na-

Ideker's team applied a rigorous statistical analysis approach
to the Fields group's Plasmodium data, focusing on interacting
proteins that have homologs in other species. While the genomes
of hundreds of species are filled with homologous proteins, Ide-
ker and his colleagues are eager to understand how they interact
with one another as part of a new approach to help in the design
of drugs that disrupt proteins in pathogens while sparing pa-
tients from side-effects.

The malaria parasite has a four-stage life cycle, and the Fields
group analyzed only the proteins expressed in the phase that in-
fects human red blood cells, an infection that leads to fever,
shaking chills, headache, muscle aches, and other symptoms. Ide-
ker said critics may fault his study because only a subset of
the Plasmodium's proteins is expressed in the erythrocytic
stage. However, he noted that the parasite's asexual-phase is
actually enriched in proteins for which homologs have been found
in other species. Ideker also noted that the known protein in-
teractions in yeast, worm, and fly represent only 20 percent of
the total interactions and some of the reported interactions may
be erroneous.

"All the protein networks described so far are incomplete and
statistically noisy," said Ideker. "But whether they are incom-
plete and noisy in the same way or not, we can say with confi-
dence that this particular stage of Plasmodium is different from
the other organisms we've examined so far. It's this lack of
overlap with other species that's surprising."

Ideker said the Plasmodium's membrane-protein complexes may be
of particular interest. "Plasmodium presents many of these pro-
teins to the red blood cell during infection and prior to repli-
cation," he said. "What really jumps out of our paper is the
large number of membrane protein interactions in Plasmodium that
are absent in other organisms. While this is potentially good
news for fighting malaria, we need to know much more before we
start talking about which membrane-protein interactions to tar-
get with a new drug."

We acknowledge the following funding support: the National Sci-
ence Foundation (S.S.); the National Institute of General Medi-
cal Sciences (T.I.); a David and Lucille Packard Fellowship
award (T.I.); the Howard Hughes Medical Institute (T.S.); and
Unilever (T.S.).

Rex Graham
University of California - San Diego 

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