‘Sweet’ polymer is asthma’s kiss of death


This schematic representation shows the polyacrylamide polymer (the spaghetti-like structure) developed by coauthor Nicolai Bovin. Attached to it is the sugar that targets the protein known as Siglec-8 that is present on the surfaces of a few types of immune cells. Researchers are hopeful the approach could be used to develop new drugs to stem allergy and asthma attacks. (Credit: © 2009 Jacqueline Schaffer)

JOHNS HOPKINS (US)—A sugar-coated polymer has been developed that selectively kills cells known to trigger aggressive allergy and asthma attacks. Scientists believe the advance could represent a significant step toward novel drug treatments.

A team led by Bruce Bochner, director of the Division of Allergy and Clinical Immunology at the Johns Hopkins University School of Medicine, has studied a unique protein known as Siglec-8 that is present on the surfaces of a few types of immune cells, including eosinophils, basophils, and mast cells, cells with diverse but cooperative roles in normal immune function and allergic diseases.

When functioning correctly, the cells help keep the body healthy and infection-free. In allergic reactions and asthma attacks, however, they unleash an overwhelming response that typically harms the body more than it helps.

The researchers had found in previous studies that when they bound antibodies that specifically target Siglec-8 to the protein on eosinophils, the cells promptly died, an effect that might be useful in stemming an allergy or asthma attack.

Since producing antibodies can be expensive—a potential roadblock to using them as pharmaceuticals in the future—the researchers sought another way to activate the protein and kill the cells.

Bochner and his colleagues discovered an unusual sugar that could uniquely and selectively attach to and activate Siglec-8 several years ago.

“The trick is that you need to engage several clusters of Siglec-8 on each cell at once to trigger cell death. You’re not going to be able to do that with individual sugar molecules in solution,” Bochner explains.

So the team has developed soft, flexible polymer strands and coated them with the sugar, “like microscopic spaghetti candy,” says Bochner.

The researchers tested the polymer’s effectiveness in several ways, including adding it to vials of whole human blood to see where the polymer attached and found it attached only to eosinophils.

Using only purified eosinophils, the researchers examined whether the polymer could kill the cells, as targeted antibodies had in previous experiments. While their results showed that the polymer killed about 65 percent of the eosinophils over 72 hours, it was not as effective as the antibody, which killed up to 90 percent of the cells in 24 hours.

“This is initial proof that delivering the sugar through a polymer can give you the desired result of selectively engaging Siglec-8 and killing eosinophils, but we still have a long way to go,” says Bochner.

He and his team plan to try to optimize these results by experimenting with other formulations to deliver the sugar to cells, including more rigid polymers, those with denser sugars, or nanoparticles coated with the sugar instead of polymers.

Researchers from the  Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry in Russia and the University of Dundee in the United Kingdom contributed to the study, which was published in the Journal of Pharmacology and Experimental Therapeutics.

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