Controlling Damaging Protein Plaques Without Side-effects: Research Could Improve Alzheimer's Medication

Researchers in the International Institute of Nano and Molecular Medicine at the University of Missouri-Columbia are studying the possible use of carboranes, which are clusters of boron and carbon atoms, to prevent such side effects. These boron-rich clusters are substituted for carbon-based benzene rings commonly found in pharmaceuticals of all types, including COX inhibitors, which give unwanted side effects.

COX activity is seen in common nonsteroidal anti-inflammatory drugs like aspirin and ibuprofen. However, prolonged use of COX inhibitors can result in a variety of negative side effects, such as possible digestive and liver problems. Some COX inhibitors have recently been pulled from the market due to an increased risk of heart complications.

The protein transythyretin acts as a shuttle to transport thyroxine, a hormone, throughout the body. As the least important of the three blood proteins that carry thyroxine, transthyretin also has a tendency to fall apart and form tough, insoluble plaques, sometimes causing injury to delicate tissues. Certain people are genetically more likely to have the proteins fall apart, increasing the risks. Investigators have found that in laboratory experiments, certain COX inhibitors help stabilize the structure of transthyretin protein, and therefore prevent harmful plaque formation.

"The successful identification of carborane-containing surrogates for known COX inhibitors based exclusively on carbon chemistry greatly strengthens the concept that carboranes can be substituted for carbon-rich portions of known pharmaceuticals, and in so doing, improve its efficacy and safety," said M. Frederick Hawthorne, professor of radiology and chemistry and director of the International Institute for Nano and Molecular Medicine.

Hawthorne and his fellow researchers have found that carboranes can be useful in staving off the negative side effects of COX inhibitors while still completing the task of preventing protein plaque buildup. Carboranes are man-made small molecules that are very stable. Because they are unnatural, the body does not recognize carboranes. This lack of recognition has the benefit of increasing drug circulation time as well as preventing the body from metabolizing the drug into potentially damaging products. Due to their unique structure, even direct carborane analogues of COX inhibitors won't act as pain relievers but will do the beneficial work of preventing protein plaque formation.

Next, researchers will test the carborane analogs with the genetic variant proteins, hoping to find the new drugs to be broadly applicable. Eventually, simple cellular tests will be performed to look for toxicity, which will then lead to the development of a simple animal model.

The technique of using carboranes and other boranes in drug development also holds promise for treating other illnesses. Like designing a set of keys that each fit only one lock, researchers hope to use carboranes to make many other drugs that are very specific and therefore reduce detrimental side effects.

"One day carboranes may become ubiquitous in the pharmaceutical industry, they are ideal candidates for further research," said Richard L. Julius, researcher at MU.

A paper detailing this research was recently published in the Proceedings of the National Academy of Sciences of the United States (PNAS). The authors include Julius, Hawthorne, Omar K. Farha, Janet Chiang and L. Jeanne Perry.