Molecular combinations keep toxic RNA from binding with MBNL1, according to Journal of the American Chemical Society study.

Using a drug discovery technique known as dynamic combinatorial chemistry, scientists at the University of Rochester Medical Center have identified several compounds that obstruct the unwanted coupling of two molecules that cause myotonic muscular dystrophy.

Earlier this decade, the research team discovered that faulty messenger RNA has a toxic effect on muscle and heart tissue. The toxic RNA binds tightly to a crucial protein known as muscle blind (MBNL1). The genetic mistake involves a repeated sequence of three chemical bases. Healthy people have anywhere from 5 to 30 copies of the triplet repeat known as CUG on chromosome 19, but people with muscular dystrophy 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 knock out their normal function.

The goal is to release 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 the research team worked to free MBNL1 by designing an experiment to search for a small molecule that would sop up extra CUG copies.

The researchers mixed two sets of 150 compounds, one on polymer beads and the other in solution, and let the components link up with each other amid CUG triplet repeat RNA strands. The technique allowed investigators to simultaneously analyze how effectively more than 11,000 molecular combinations could bind to the target CUG RNA strand.

Investigators then sorted out which combinations muscled out the others for access to RNA strands and held most tightly to them. The team then took the best performers and put them in a solution containing both CUG triplet repeat RNA strands and MBNL1. The group’s molecules were able to break up the interaction between the two, with the best molecules freeing up to half the MBNL1. The team is now continuing its work, further refining the molecules in an attempt to find one that frees MBNL1 even more effectively.

This article was published online in the Journal of the American Chemical Society.

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