The genetic mistake involves a repeated sequence of three chemical bases. Healthy people have anywhere from five to 30 copies of the "triplet repeat" known as CUG on chromosome 19, but people with the disease typically have hundreds or thousands of copies, a kind of molecular stutter. These extra copies become part of large, faulty messenger RNA molecules that can mistakenly glom onto proteins and knockout their normal function.
Earlier this decade, Thornton's team discovered that the faulty messenger RNA has a toxic effect on muscle and heart tissue. The team found that the toxic RNA binds tightly to a crucial protein known as "muscle blind" or MBNL1 and prevents that protein from performing its usual function, ultimately leading to the muscle symptoms of muscular dystrophy.
The goal for doctors is to free up MBNL1 in cells so that it can go about its normal activities, which include building proper chloride channels that are central to normal muscle function.
So Miller set out to free MBNL1 by designing an experiment to search for a small molecule that would sop up extra CUG copies. Using a technique known as dynamic combinatorial chemistry, Miller mixed two sets of 150 compounds, one on polymer beads and the other in solution, and let the components link up with each other in a kind of molecular dance, amid a sea of CUG "triplet repeat" RNA strands. The technique, which Miller helped to pioneer more than a decade ago, allowed him to simultaneously analyze how effectively more than 11,000 molecular combinations could bind to the target CUG RNA strand.
Miller's team sorted out which combinations muscled out the others for access to RNA strands and held most tightly onto them. The team then took the best performers
|Contact: Tom Rickey|
University of Rochester Medical Center