Chloride-transporting synthetic molecules show promise
Normal mucus production restored in a cell model of cystic fibrosis, study shows
Researchers have developed new synthetic molecules that can transport chloride salts across cell membranes, which showed promise for restoring normal mucus production in a cell model of cystic fibrosis (CF), a new study shows.
“One day, [these molecules] could be leveraged into a drug that treats cystic fibrosis,” Bing Gong, PhD, lead author of the study at the University at Buffalo in New York, said in a press release.
The study, “Aromatic pentaamide macrocycles bind anions with high affinity for transport across biomembranes,” was published in Nature Chemistry.
CF is caused by mutations that hinder the function or production of the CFTR protein. Normally, this protein sits in the membrane of cells and regulates the flow of chloride in and out of the cell. When the protein isn’t working in CF, it results in abnormally thick and sticky mucus that causes most disease symptoms.
Chloride is an ion or salt molecule — one half of sodium chloride, or table salt. More specifically, chloride is an anion, meaning it’s a salt molecule that carries a negative electrical charge.
Theoretically, artificial molecules that allow chloride anions to flow across the cell membrane could essentially replace the normal function of the CFTR protein and be used to treat CF. However, while chemists have figured out strategies for making synthetic molecules that bind to positively-charged salts (called cations), it’s generally much harder to make synthetic molecules that can stick to negatively-charged anions like chloride.
“Synthetic anion binding is much more challenging because anions can be all kinds of shapes — spherical, octahedral, even tetrahedral. It’s hard to tailor-make clothes for them, so to speak,” Gong said.
Making artificial chloride channels using macrocycles
Here, the researchers figured out how to make artificial chloride channels using macrocycles, a type of molecule defined by a particular ring-like structure. The scientists determined they could arrange several macrocycles together in five-pointed shape like a star, with certain specific chemical groups pointing in toward the center in just such a way that chloride ions can slide through.
“Our computations were able to provide a deeper understanding of the orientation and positioning of the macrocycle relative to chloride,” said study co-author Daniel Miller, PhD, a Buffalo graduate who is now a professor at Hofstra University in New York.
In a series of lab experiments, the researchers showed that when the macrocycle structure was inserted into a cellular membrane, it could facilitate the flow of chloride anions across the membrane.
“The interior of a cell membrane is hydrophobic — it doesn’t like positively or negatively charged ions — but our macrocycles actually gave anions a hydrophobic shield so they can travel to the other side of the cell membrane,” Gong said.
Macrocycles also tested in lung cell model of CF
The team also tested the macrocycles in a lung cell model of CF. In this model, the defect of CFTR protein results in less airway surface liquid, a thin layer of fluid coating the surface of airway cells. The team found that treatment with the macrocycles increased this liquid, an effect that would be expected to translate to thinner mucus in people with CF.
“We found that these molecules can serve as an effective ferry to transport chloride across the cell and therefore restore the level of airway surface liquid, or ASL, to essentially that of a normal,” Gong said.
“It is exciting when scientific discoveries can be applied in ways that will potentially improve the health and well-being of people with complex conditions like cystic fibrosis that have limited treatment options,” Miller said.
Beyond CF, the researchers said this macrocycle-based platform could serve as the basis to target other types of anions.
“Based on this structurally tunable platform, the development of the next-generation anion binders, transporters and potential therapeutics for channel-related diseases can be envisioned,” the scientists concluded.
“Developing new treatments for cystic fibrosis treatment remains a crucial effort. Our research in anion and cation binding can apply to not only cystic fibrosis, but a host of other channel diseases caused by defective ion channels,” Gong said.
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