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 Angewandte Chemie, reports the creation of small molecules 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 RNA interference (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 gene expression can be controlled by triggering the degradation of messenger RNA—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 hydroxyl radicals. 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 small molecules involved were well defined.
The study, “Small Molecule-Mediated Cleavage of RNA in Living Cells,” was supported by the National Institutes of Health (Grant number: R01-GM079235) and TSRI. For more information on the study, see http://onlinelibrary.wiley.com/doi/10.1002/anie.201206888/abstract.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, TSRI has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
Office of Communications
Eric Sauter | Source: EurekAlert!
Further information: www.scripps.edu
More articles from Life Sciences:
New way to improve antibiotic production
18.06.2013 | Norwich BioScience Institutes
Missing enzyme linked to drug addiction
18.06.2013 | The Endocrine Society
... two engines aircraft project “Elektro E6”.
The countdown has been started for opening the gates again for the worldwide leading aviation and space event in Le Bourget, Paris from June 17th - 23rd, 2013.
EADCO & PC-Aero will present at the Paris Air Show in Hall H4 booth F-7 their new future aircraft and innovative project: ...
Siemens scientists have developed new kinds of ceramics in which they can embed transformers.
The new development allows power supply transformers to be reduced to one fifth of their current size so that the normally separate switched-mode power supply units of light-emitting diodes can be integrated into the module's heat sink.
The new technology was developed in cooperation with industrial and research partners who ...
Cheaper clean-energy technologies could be made possible thanks to a new discovery.
Led by Raymond Schaak, a professor of chemistry at Penn State University, research team members have found that an important chemical reaction that generates hydrogen from water is effectively triggered -- or catalyzed -- by a nanoparticle composed of nickel and phosphorus, two inexpensive elements that are abundant on Earth. ...
The Fraunhofer Institute for Laser Technology ILT generated a lot of interest at the LASER World of Photonics 2013 trade fair with its numerous industrial laser technology innovations.
Its highlights included beam sources and manufacturing processes for ultrashort laser pulses as well as ways to systematically optimize machining processes using computer simulations. There was even a specialist booth at the fair dedicated to the revolutionary technological potential of digital photonic production.
Now in its fortieth year, LASER World ...
It's not reruns of "The Jetsons", but researchers working at the National Institute of Standards and Technology (NIST) have developed a new microscopy technique that uses a process similar to how an old tube television produces a picture—cathodoluminescence—to image nanoscale features.
Combining the best features of optical and scanning electron microscopy, the fast, versatile, and high-resolution technique allows scientists to view surface and subsurface features potentially as small as 10 nanometers in size.
The new microscopy technique, described in the journal AIP Advances,* uses a beam of electrons to excite a specially ...
18.06.2013 | Materials Sciences
18.06.2013 | Health and Medicine
18.06.2013 | Life Sciences
14.06.2013 | Event News
13.06.2013 | Event News
10.06.2013 | Event News