New Compound Corrects Badly Behaved RNA | Chemical & Engineering News
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Web Date: January 26, 2012

New Compound Corrects Badly Behaved RNA

Targeting RNA: Small molecule binds to trinucleotide repeats associated with Huntington’s disease
Department: Science & Technology
News Channels: Biological SCENE
Keywords: RNA repeats, drug design, RNA processing, genetic disorder, Huntington’s disease, Fragile X syndrome, myotonic dystrophy
Repeat Binder
The molecule 4-guanidinophenyl 4-guanidinobenzoate binds CAG repeats in RNA and prevents RNA processing errors.
Credit: Matthew Disney
4-guanidinophenyl 4-guanidinobenzoate.
Repeat Binder
The molecule 4-guanidinophenyl 4-guanidinobenzoate binds CAG repeats in RNA and prevents RNA processing errors.
Credit: Matthew Disney

In diseases such as Huntington’s, myotonic dystrophy, and Fragile X syndrome, repeating nucleotide sequences cause cell-wide havoc by gumming up RNA processing. As a result, chemists would like to develop drugs to silence these nucleotide stutters. Unfortunately, designing small molecules to bind specific RNA sequences is tough. Now researchers have identified one of the first compounds that can prevent RNA processing errors in cells by binding a specific RNA repeat sequence. (ACS Chem. Biol., DOI: 10.1021/cb200413a).

Unlike proteins, RNAs are very flexible and packed with negative charge. Both characteristics tend to thwart chemists’ desire to develop small molecules that bind tightly to specific sequences. When designing compounds to target ribosomal RNA, researchers can start from crystal structures of known molecules bound to the nucleic acids. But no such information exists for most messenger RNA sequences.

Matthew D. Disney, a chemist at the Scripps Research Institute in Jupiter, Fla., and his colleagues wanted to find compounds that could bind a repeating CAG trinucleotide sequence associated with Huntington’s disease. This repeat causes the RNA to fold into a structure that binds to an RNA-processing protein called muscleblind-like 1. When multiple copies of muscleblind-like 1 glom onto the repeats, the cell’s machinery can’t process RNA correctly.

To find small molecules that would bind the CAG repeat and thereby block the processing protein from attaching, the researchers first tested whether molecules known to interact with nucleic acids would recognize CAG. Those tests pointed to a molecule

called 4’,6-diamidino-2-phenylindole. But when the chemists tested the molecule on human cell lines, they found it killed all the cells.

So Disney’s team next searched for molecules that were similar in shape and electrostatics in the National Cancer Institute’s 250,000-compound library. Of the nine best matches, only one, 4-guanidinophenyl 4-guanidinobenzoate, could selectively bind CAG repeats and did not kill human cells even in high concentrations. It was also the most potent inhibitor of muscleblind-1 binding. When the scientists applied the molecule to connective tissue cells with the Huntington’s disease mutation, they found that RNA processing errors disappeared.

Steven C. Zimmerman, of the University of Illinois, Urbana-Champaign, calls the discovery promising: “Finding compounds that bind oligonucleotides is easy, but finding agents that are selective is difficult.” He says that the researchers’ screen could help design ligands for other RNA targets.

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Edibell Stone (January 27, 2012 5:47 AM)
Thank you for your very important work! It gives me hope for my family with myotonic dystrophy.
Edibell Stone
Raman Parkesh, PhD (January 27, 2012 1:12 PM)
Thanks for this comment. It is very interesting work. This shows the power of the interdisciplinary research can do to tackle basic science. We used computational 3D shape methods to find novel analogs of DAPI using NCI database molecules using software such as Omega and ROCS from openeye. We begin with the 4,6-diamido-2-phenylindole, but it was toxic. Rather then modifying using time consuming and laborious organic synthetic methodology, we used ligand-based virtual screening methods to identify novel novel analog for this query molecules. We were able to link these computational methods to the freely available database from NCI. We are also grateful to Openeye and ChemAxon for providing free academic software, which made this work possible.

Hopefully with the advances in computational modelling, it will be possible to develop drugs targeting selectively various RNA mediated disease.
Matt (February 1, 2012 9:19 PM)
I also want to thank you for your research. Every few days I search for news on the net about Huntington's disease treatment research. My wife has HD and after reading about this breakthrough, it also gives me hope that she'll have an effective treatment before she gets too sick. Thanks again!


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