New Drugs May Block Muscular Dystrophy's Toxic RNA

A research team seeking drugs to treat muscular dystrophy have used techniques from the realm of dynamic combinatorial chemistry to identify several promising compounds.

Dynamic combinatorial chemistry integrates synthesis of chemical libraries and screening in one process, potentially accelerating the discovery of useful compounds. In the dynamic approach, the libraries are not created as arrays of individual compounds, but are generated as mixtures of components, similar to natural pools of antibodies. One important requirement is that the mixture components exist in dynamic equilibrium with each other. According to basic laws of thermodynamics, if one of the components is removed from the equilibrated mixture--by binding to the target molecule, for example--the system will respond by producing more of the removed component to maintain the equilibrium balance in the mixture.

The dynamic mixture, as any other combinatorial library, is so designed that some of the components have potentially high affinity to a bio-molecular target. These high-affinity components can form strong complexes with the target. If the target is added to the equilibrated mixture, when the effective components form complexes with the target they are removed from the equilibrium. This forces the system to make more of these components at the expense of other ones that bind to the target with less strength. As a result of such an equilibrium shift, the combinatorial library reorganizes to increase the amount of strong binders and decrease the amount of the weaker ones. This reorganization leads to enrichment of the library with the effective components and simplifies their identification.

In the current study, investigators at the University of Rochester Medical Center (New York, NY, USA) used dynamic combinatorial chemistry to seek compounds that would prevent the binding of muscular dystrophy's characteristic toxic RNA – with hundreds or even thousands of CUG base repeats – to the splicing regulator protein MBNL1.

They reported in the November 8, 2008, online edition of the Journal of the American Chemical Society that the method allowed the simultaneous testing of 11,000 compounds and yielded several molecules with significant selectivity for binding to CUG repeat RNA.

"The drug discovery field really is wide open when it comes to RNA, which is a very difficult molecule to target,” said senior author Dr. Benjamin Miller, associate professor of biochemistry and biophysics at the University of Rochester Medical Center. "This discovery gives us, for the first time, a molecule that targets the wayward RNA at the root of myotonic muscular dystrophy. This is a first step toward developing a drug-like molecule that perhaps could be used someday to treat the disease. This lead molecule provides a framework for moving forward.”

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University of Rochester Medical Center