Wednesday, May 7, 2014

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

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