Scientists from the Florida
campus of The Scripps Research Institute have identified a compound that can
help repair a specific type of defect in RNA. The methods in the new study
could accelerate the development of therapeutics to treat a variety of
incurable diseases such as Huntington’s disease, spinocerebellar ataxia, and
Kennedy disease.
The new study, published in ACS Chemical Biology, describes a method
to find compounds that target defective RNAs, specifically RNA that carries a
structural motif known as an “expanded triplet repeat.” The triplet repeat, a
series of three nucleotides repeated many more times than normal in the genetic
code of affected individuals, has been associated with a variety of neurological
and neuromuscular disorders.
“For a long time it was thought that only the protein translated from this
type of RNA was toxic,” said Matthew Disney, an associate professor at Scripps Florida who led the new
study. “But it has been shown recently that both the protein and the RNA are
toxic. Our discovery of a small molecule that binds to RNA and shuts off its
toxicity not only further demonstrates that the RNA is toxic but also opens up
new avenues for therapeutic development because we have clearly demonstrated
that small molecules can reverse this type of defect.”
In the new research, the scientists used a query molecule called 4′,
6-diamidino-2-phenylindole (DAPI) as a chemical and structural template to find
similar but more active compounds to inhibit a toxic CAG triplet repeat. One of
these compounds was then found effective in inhibiting the RNS toxicity of the
repeat in patient-derived cells, which demonstrated an improvement in
early-stage abnormalities.
“The toxic RNA defect actually sucks up other proteins that play critical
roles in RNA processing, and that is what contributes to these various
diseases,” Disney said. “Our new compound targets the toxic RNA and inhibits
protein binding, shutting off the toxicity. Since the development of drugs that
target RNA is extremely challenging, these studies can open up new avenues to
exploit RNA drug targets that cause a host of other RNA-mediated diseases.”
Disney and his colleagues are already hard at work to extend the laboratory’s
findings.
The lead author of the study, “Chemical Correction of Pre-mRNA Splicing
Defects Associated with Sequestration of Muscleblind-Like 1 Protein by Expanded
r(CAG)-containing Transcripts,” is Amit Kumar of Scripps Research.
