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Another Step Along the Way from Discovery to Treatment
Study Identifies Peptides that Can Change the Rate of Iron Transport

"We had been measuring how fast the iron was coming out by using a chelator, which led us to wonder whether we couldn't chemically link that chelator, in this case, desferal, to the peptide, and get the iron out even faster."

For many years, CHORI Senior scientist, Elizabeth Theil, PhD, has been pioneering research discoveries regarding ferritin, the nanoprotein responsible for concentrating iron in the body’s cells. While Dr. Theil had already discovered the existence of gated pores within the normally stable ferritin structure, as well as how they affect the speed of iron removal from ferritin for the cell and body to use, now Dr. Theil and her colleagues have identified two previously unknown peptides that can control the opening and closing of the pore gates.

“Phage display is a technique that allows you to search over a billion peptides to find one or two that might bind a target, such as the ferritin pore gates” Dr. Theil explains. “We took ferritin and mixed it with these peptides, and by a variety of techniques, were able to find a small number – 5 – that bound to ferritin quite tightly. Three had no effect, but two had very big effects.”

The first of the 2 peptides resulted a 3 times faster increase in removing iron to chelators, the iron-binding drugs used in medicine, suggesting that the peptide caused the gated pores to open. The results, published in November's Journal of Biological Chemistry, were even more dramatic when the chelator was connected directly to the peptide.

In fact, the result was an 8-fold increase, most likely due, Dr. Theil believes, to being able to bring the chelator directly to the gated pores. The second of the 2 peptides had the completely opposite effect, slowing down the rates of chelation - by 60 percent.

"What we think is that in life, there are probably two proteins, one which opens the pores and one which closes them, and that the cell makes these proteins depending on whether it needs to use the iron or keep the iron inside," says Dr. Theil.

Controlling when the gates in the ferritin pores open or close is key to controlling iron transport, and essential to treating iron overload in disease like sickle cell disease and thalassemia. In these diseases, iron in the regular blood transfusions that are crucial to health turn into extra iron in ferritin that needs to be removed to make room for iron from the next transfusions.
"The chelator drugs that are now available for treating children who get regular blood transfusions work very slowly. If you can target the chelator right to the ferritin pores, you certainly get the iron out faster, and you get a lot more bang for your buck."
Being able to slow down iron transport rates could also be useful, such as when a patient is fighting an infection.

"Bacteria need iron to grow," Dr. Theil says, "so keeping iron locked up during an infection helps to fight off the bacteria."

While both these peptides represent a breakthrough in the potential for the development of new drugs targeting iron transport rates, Dr. Theil is quick to point out that she couldn't have predicted how significant the results would be in advance.

"Most of the work I do is discovery," she says. "If I knew what I would find before I started, there would be no need to do it. What we hoped was that we might be able to increase rates of iron chelation, which we did. The other peptide was a complete surprise. But the most exciting part of research is when Nature turns out to be way ahead of you and you find something didn't expect to find."

More work is still ahead in order to take these discoveries from lab to clinic - the end goal. Dr. Theil hopes to be able to identify the natural proteins themselves and to create a drug that is safe and effective in people.
In the mean time, however, in a prestigious turn of events, Science Magazine has selected the publication as one of its Editor's Choice picks for the month.

"It suggests that the editors of Science think this is something worth talking about. We were very pleased that they were as excited about it as we are," Dr. Theil says.

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Monday, May 16, 2011 11:33 PM

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