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Small molecule blocks aberrant pathway associated with myotonic dystrophy

July 10, 2017

"They don't have a normal function, so it's okay to bind to those repeats," she said. "You certainly don't want to target the protein because you want it to go perform its normal function."

In the course of basic research into compounds that bind to DNA or RNA, the researchers designed a molecule that would selectively bind to T-T or U-U mismatches in DNA or RNA, respectively. (Mismatches occur when two nucleotides in a double-stranded molecule are improperly paired, as occurs in the CTG repeats in the mutant DNA and the CUG repeats in the RNA.) Their compound, which they call Ligand 1, binds to the region of excessive repeats in both the RNA and DNA from the aberrant DMPK gene. More importantly, Ligand 1 prevents the MBNL protein from binding to the RNA.

Further tests revealed that the new compound has significantly lower affinity for other mismatches in DNA or RNA. Baranger's lab also tested the compound on other normal protein-RNA complexes, and found that it did not disrupt those interactions.

This last finding was critical, Zimmerman said.

"The danger is if you make something that binds to RNA or DNA, it's going to bind to all these other molecules and disrupt those complexes, so you help one problem but you cause all these others. Our molecule doesn't do that."

Source: University of Illinois at Urbana-Champaign