2:45 PM
 | 
Jun 08, 2017
 |  BC Innovations  |  Targets & Mechanisms

Pumping iron

A new small molecule for iron deficiency diseases

A natural compound from the Japanese Hinoki tree may hold the answer to iron transport diseases treated inadequately by phlebotomy, chelation therapy or dietary supplements. In Science last month, a University of Illinois-led group reported that the small molecule hinokitiol can replace defective iron transport proteins, and move iron in and out of cells.

The team plans to test the molecule in the clinic, and is generating derivatives both to optimize and better understand its properties.

And beyond the study’s therapeutic implications, the authors believe their screening strategy could become a general platform for discovering ion transport modulators.

Movement of iron around the body involves a complex system of active and passive transporters with varied expression patterns, subcellular locations and directional transport. Iron absorbed from food is transported across the gut epithelium to blood, where it is moved by plasma proteins to the bone marrow for new blood cell production and into other organs for a variety of metabolic roles.

Although there are at least 25 genetic diseases associated with defects in iron transport or metabolism, no therapies in the clinic are capable of substituting for any of the three primary human active iron transporters - SLC11A2, SLC40A1 and mitoferrin.

Mutations in SLC40A1 cause the iron overload disorder hemochromatosis type 4; mutations in SLC11A2 have been linked to rare cases of hypochromic microcyclic anemia; and mutations in mitoferrin have been linked to the skin disorder erythropoietic protoporphyria.

According to University of Illinois professor Martin Burke, who led the study, a defect in any one transporter can cause a local buildup of iron that creates a gradient across the membrane.

That suggested to his team that a small molecule that can move iron in response to gradients might be able to restore transport regardless of whether the direction of transport is into, out of, or within cells.

The group reasoned that an unbiased search for molecules that restored iron function by any mechanism might yield therapies that are not only new but safer than those available for iron deficiency or overload diseases. Although iron overload is typically treated with chelators that bind the ion in the plasma, the drugs can cause serious gastrointestinal side effects.

Burke’s approach was to create highly specific buildups of iron in yeast by individually deleting the three transporters, which move iron in different directions across different membranes, and then screen for molecules that could dissipate the resulting iron gradients.

“You don’t need a perfect mimic of a missing protein in order to restore physiology, you just need something that can...

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