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Paulette Royt, chair and associate professor of Biology, in her lab where
she isolated a novel iron chelator called pseudan.
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Novel Iron Chelator Could Provide Breakthrough in Chelator Therapy
By Lynn Burke
The presence of too much iron in a person’s blood can be just as unhealthy
as extremely low levels of iron. To remove the excess iron, patients must undergo
therapy that uses chelators, molecules to which the iron will bind. Bound to the
chelator, iron will eventually be eliminated from the body. Unfortunately, this
treatment is difficult and painful. The isolation and synthesis of a novel iron
chelator called pseudan by Paulette Royt, chair and associate professor of Biology,
and her colleagues, however, may lead to development of a chelation therapy that
patients could more easily tolerate.
While studying pyoverdine, a well-known iron-chelating compound that is secreted
by the bacterium Pseudomonas aeruginosa, Royt isolated another iron-binding
compound, pseudan, from the cytoplasmic membrane of this organism. She then purified
the compound using reverse-phase high-performance liquid chromatography and determined
its structure: 4-hydroxy-2-nonylquinoline. She and her research team were able
to synthesize the molecule and show that the properties of the synthesized compound
and the purified compound were nearly identical.
Royt says that pseudan was first isolated 50 years ago, but at the time no
one could determine its function. She believes pseudan stores iron because the
chelator is found in P. aeruginosa when the bacterium is grown in medium
that is high in iron. “By storing the excess iron, iron toxicity of the bacterial
cell is prevented,” she explains.
Excess iron can occur in humans for a number of reasons including the presence
of hemolytic anemia, hereditary or secondary hemochromatosis, or hepatitis, says
Royt. In addition, regular blood transfusions administered to treat anemia can
cause the body to retain too much iron. Iron overload can cause microbial infection,
cardiomyopathy, arthropathy, neoplasia, and certain endocrine disorders, explains
Royt. Excess iron also lowers the immune system and has been found to trigger
or exacerbate Alzheimer’s disease, multiple sclerosis, Parkinson’s disease,
among other conditions, according to the Iron Overload Diseases Association.
“Currently, desferrioxamine B is the only hyperferremic drug available
for chelation therapy of iron overload,” says Royt. “The problem with
this drug is that it must be administered intravenously, and its side effects
include hypotension, growth retardation, and neurological effects.” According
to the Cooley’s Anemia Foundation web site (www.thalassemia.org),
this method of chelation therapy involves infusing the drug through a small battery-operated
pump worn under the skin of the stomach or legs five to seven times a week for
up to 12 hours. The web site states that this treatment method is so difficult
that many patients do not keep up with the therapy—a decision that can worsen
a patient’s condition and prove fatal.
Royt believes that the synthetic pseudan her team produced could be developed
into an oral drug for chelation therapy. Because pseudan’s long hydrophobic
chain binds to lipids, the molecule could be inserted into an artificial lipid
vesicle. If the functional iron-binding groups were exposed on the exterior of
the lipid vesicle after insertion, the chelator would retain its iron-binding
property. Pseudan could then be administered orally, passing through the stomach
to the intestines where it would enter the bloodstream. Once in the blood, pseudan
is expected to bind with iron.
The possibility of treating iron overload with a pill instead of with painful
infusion therapy could make further research with the synthetic pseudan attractive
to pharmaceutical manufacturers, Royt believes. Currently, Jennifer Murphy, director
of George Mason’s Office of Technology Transfer, is seeking a company to
pursue this research further with Royt and her team with the ultimate goal of
developing a more patient-friendly treatment for iron overload.
Royt, who has been doing research on iron chelators for 15 years, was joined
in this latest effort by Bob Honeychuck and Wayne Stalick of George Mason’s
Chemistry Department. Other collaborators include researchers from the U.S. Department
of Agriculture and the National Institutes of Health and many undergraduate and
graduate Biology and Chemistry students. The results of this research will be
published in Bioorganic Chemistry.
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