Molecules Developed for Treatment of Muscular Dystrophy

August 7, 2012 § Leave a comment

Scientists from the Florida campus of The Scripps Research Institute have published two findings in the online-before-print edition of Journal of the American Chemical Society and ACS Chemical Biology that are of great interest to those suffering from adult-onset muscular dystrophy. For the first time, researchers have developed a series of small molecules that act against the one RNA defect that is responsible for the most common form of the medical condition.

The small molecule compounds were found to drastically improve various biological defects associated with myotonic dystrophy type 1 (MD1) in both cell cultures and animal subjects. Matthew Disney, PhD, associate professor at Scripps Research Institute said, “Our compounds attack the root cause of the disease and they improve defects in animal models. This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general.”

MD1 is the result of an RNA defect called a “triplet repeat.” This is a sequence of three nucleotides, cytosine-uracil-guanine (CUG), in an individual’s genetic code that are repeated an abnormal and excess number of times. Repetition of these nucleotides in RNA initiates MD1 by binding to and deactivating MBNL1, a specific protein. The resulting abnormality is a continuous splicing of the proteins. This can affect the muscles, causing them to desecrate and waste away.

The researchers involved in the studies utilized data within the RNA motif-small molecule database that the group had been building to locate compounds that are hostile to the problem RNA implicated in the disease. They queried the database against the secondary structure of the triplet repeat that causes the disorder. The chief compound affecting this RNA was found with ease. Afterwards, these compounds were assembled in such a way as to target the increased repeat, or in some cases they were simply optimized. One of the compounds improved the protein-splicing defect by more than 40 percent in an animal subject.

As for the future of this research, Disney commented, “There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them. We’ve answered that question by rationally designing these compounds that target this RNA. There’s no reason that other bioactive small molecules targeting other RNAs couldn’t be developed using a similar approach.”




Works Cited

“Research Scientists Create Potent Molecules Aimed at Treating Muscular Dystrophy”. (February 22, 2010). Neuroscience News. March 2, 2012.



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