Scientists create new approach to destroy disease-associated RNAs in cells

December 20, 2012

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have developed a new approach to alter the function of RNA in living cells by designing molecules that recognize and disable RNA targets. As a proof of principle, in the new study the team designed a molecule that disabled the RNA causing myotonic dystrophy.

The study, published online ahead of print on December 20, 2012 by the journal , reports the creation of small that recognize disease-associated RNAs, targeting them for destruction. Since small molecules are cell-permeable, the approach could have benefits over traditional methods of targeting RNAs for degradation, such as antisense or (RNAi).

"We're excited about these results," said Matthew Disney, an associate professor at TSRI who pioneered the research. "This approach may allow for the inactivation of many cellular RNAs by small molecules and potentially lead the way to a whole range of novel therapeutics."

It's well known that can be controlled by triggering the degradation of —the blueprint for the production of proteins. This is accomplished through the recruitment of compounds that cleave or split the molecule. While several compounds can induce RNA cleavage in vitro, this has not been accomplished efficiently in living cells—until now.

In the new study, Disney and Research Associate Lirui Guan attached a rationally designed small molecule that targets the RNA that causes myotonic dystrophy type 1 with a molecule that produces . Upon the small molecule's recognition of the target, a hydroxyl radical was released that cleaved the disease-associated RNA, alleviating the disease-associated defects. Disney noted that, despite the compound's producing a highly reactive species, the compounds are non-toxic at relatively effective doses.

The team accomplished this feat through what Disney calls a bottom-up approach to targeting RNA.

"We first identified the preferred RNA structural elements or motifs that bind to small molecules," he said. "Then we looked at these elements in RNAs that cause disease and designed a binding molecule with increased affinity and specificity for those elements."

Myotonic dystrophy type 1 involves a type of RNA defect known as a "triplet repeat," a series of three nucleotides repeated more times than normal in an individual's genetic code, resulting in a number of protein splicing abnormalities. Symptoms of this variable disease can include wasting of the muscles and other muscle problems, cataracts, heart defects and hormone changes.

The applications for this new approach could include cancer treatment in conjunction with other therapies, Disney said. The approach could also be used to create chemical probes of RNA function or to develop tools to probe RNA structure—provided, of course, that the RNA-binding preferences of the involved were well defined.

Explore further: Chemists Rationally Design Inhibitors Against an RNA Molecule that Causes Myotonic Muscular Dystrophy

More information: "Small Molecule-Mediated Cleavage of RNA in Living Cells," onlinelibrary.wiley.com/doi/10.1002/anie.201206888/abstract

Related Stories

Scientists create novel RNA repair technology

January 18, 2012

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, a type of genetic material. The methods in the new study could accelerate ...

Recommended for you

Room-temperature lithium metal battery closer to reality

February 4, 2016

Rechargeable lithium metal batteries have been known for four decades to offer energy storage capabilities far superior to today's workhorse lithium-ion technology that powers our smartphones and laptops. But these batteries ...

Uncovering secrets of elastin's flexibility during assembly

February 5, 2016

Elastin is a crucial building block in our bodies - its flexibility allows skin to stretch and twist, blood vessels to expand and relax with every heartbeat, and lungs to swell and contract with each breath. But exactly how ...

Researchers seek efficient means of splitting water

February 5, 2016

Photovoltaics promise to help meet our energy needs by turning sunlight into electricity. We can't run everything that way, but with a little tweaking, photovoltaic materials can use solar energy to split water into hydrogen ...

Antibiotic's killer strategy revealed

February 4, 2016

Using a special profiling technique, scientists at Princeton have determined the mechanism of action of a potent antibiotic, known as tropodithietic acid (TDA), leading them to uncover its hidden ability as a potential anticancer ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.