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Drugs designed to target specific forms of iron might become disease fighters

Abnormal levels of a form of iron rise in the blood upon infection with parasites such as the ones behind malaria. Now scientists reveal they can design drugs that target this iron, report findings detailed in the Proceedings of the National Academy of Sciences that could help fight not only malaria, but other diseases involving abnormal levels of this form of iron, potentially including cancer.

Iron exists in a variety of oxidation states in the body — states representing how many electrons an iron atom has lost or gained when bound inside a compound. Most iron in the body is present in the ferric iron(III) state, but disease often causes unbound, reactive ferrous iron(II) to form. For example, when malaria parasites invade red blood cells, they devour the hemoglobin that helps blood carry oxygen, generating abnormally large amounts of ferrous iron as a toxic byproduct.

Medicinal chemist Adam Renslo at the University of California, San Francisco, and his colleagues reasoned drugs that prefer ferrous iron could target infected cells while ignoring healthy ones, thereby limiting unwanted side-effects. The researchers took a molecule that malaria parasites find highly toxic and attached it to a compound that serves as a delivery vehicle, fragmenting in response to ferrous iron. Scientists think a similar fragmentation occurs with commonly used antimalarial drugs known as artemisinins.

In experiments testing these new compounds in mice infected with a mouse version of malaria, Renslo and his colleagues found it selectively targeted infected cells for improved efficacy. It also greatly reduced unwanted side-effects against peripheral organs such as the liver and spleen.

“These are proof-of-concept molecules,” Renslo says. “We don’t intend these specific molecules to move toward the clinic — we’re just establishing the concept.”

To eliminate malaria from populations, mass drug administration campaigns with antimalarial drugs have been carried out before, dosing both patients with symptoms of malaria and people without them. One problem with such campaigns is that antimalarial drugs have to be safe for uninfected people. “If we can use compounds that require activation by ferrous iron, uninfected people can potentially be saved from any side-effects of the drugs,” Renslo says.

In addition to malaria, the researchers suggest this strategy could work against other diseases involving aberrant levels of reactive ferrous iron. Obvious candidates include other blood-feasting parasites, such as those responsible for schistosomiasis.

Moreover, “artemisinins have been studied extensively in cancer cell lines, where they’re not as potent as they are against malaria, but they do show some activity, so some have suggested they might be relevant against cancer,” Renslo says. This suggests certain cancers might lead iron-related metabolic pathways to malfunction, “and so our strategy may be useful against cancers as well.”

Categories: Medical Sciences
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