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Rules to Target RNA Are Focus of Research

19.12.2005


Once described as DNA’s less-famous chemical cousin, RNA, or ribonucleic acid, recently has moved to center stage.



RNA, the genetic material that circulates throughout cells, orchestrates the building of proteins based on instructions provided by DNA, catalyzes chemical reactions and can alter expression of proteins that may lead to cancer and other diseases.

But finding compounds that bind to and inhibit an RNA sequence -- as a potential new approach to designing disease treatments -- is still very much a trial-and-error process, involving the tedious screening of millions of molecules against a single RNA sequence.


Now, a University at Buffalo medicinal chemist is hoping to change that.

Matthew D. Disney, Ph.D., assistant professor in the Department of Chemistry in UB’s College of Arts and Sciences, is working to develop rules for targeting RNA. These rules could be used in the rational design of compounds to inhibit a specific RNA sequence.

Disney’s goal, with the help of a five-year, $50,000 new faculty award from the Camille & Henry Dreyfus Foundation, is to develop a chemical code to enable rational design of binders to any RNA structure. His work also is funded by the New York State Center of Excellence in Bioinformatics and Life Sciences.

"What we would like to do is develop a general set of tools that can take an RNA sequence and design efficiently a compound that can turn its activity off," explained Disney.

The human genome and other sequencing efforts have uncovered a lot of sequence information, he continued, but the question, he asks, is, "How can that information be best exploited?"

"One answer may be to take RNA sequence information and design drugs that target that sequence," said Disney. "If that can be done, then a lot of the expense in designing new drugs goes out the window."

Potentially, that could facilitate the development of compounds to treat diseases ranging from antibiotic-resistant bacterial infections to cancer and genetic diseases, such as sickle cell anemia and cystic fibrosis, Disney said.

Rationally designed RNA inhibitors could, he explained, prove more valuable than molecules that inhibit DNA.

One reason is that while DNA bases or nucleotides are always paired according to the same formula, RNA bases have more diverse pairings, which makes targeting RNA more challenging, but also potentially more valuable.

"The ability to form different pairings allows RNA to have a much larger structural repertoire than DNA and that gives RNA the ability to have such diverse cellular functions," said Disney.

In addition, he said, because DNA is present only in the nucleus, pharmaceutical compounds that target it must be able to penetrate the nucleus.

"Since RNA is present both in the cell’s nucleus and cytoplasm, you do not need to get a compound into the nucleus to target it," he said.

Because RNA folds more like a protein than DNA does, it also may be easier to design compounds that selectively target specific structures, he added.

Disney lives in Williamsville.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York.

Ellen Goldbaum | EurekAlert!
Further information:
http://www.buffalo.edu

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