Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Small Molecule Inhibits Pathology Associated With Myotonic Dystrophy Type 1

08.09.2009
Researchers at the University of Illinois have designed a small molecule that blocks an aberrant pathway associated with myotonic dystrophy type 1, the most common form of muscular dystrophy.

The new compound, soon to be tested in cells, binds tightly to its target, an abnormally elongated RNA that hijacks part of the normal cellular machinery and brings on symptoms of the disease. The newly developed compound is the first to show high selectivity in binding the target while not disrupting other important RNA functions. The study appears this week in the Proceedings of the National Academy of Sciences.

Myotonic dystrophy type 1, a muscle degeneration disease that so far is untreatable, affects about one in 8,000 people worldwide. Some cases are mild, but others lead to a debilitating loss of muscle control, declines in organ function and other potentially life-threatening conditions.

Scientists have recently identified a primary causative agent of the disease, a mutant version of a gene, called DMPK, which contains an excessive number of tri-nucleotide repeats. Nucleotides are the chemical letters that spell out the sequence of a gene, and the normal version of the DMPK gene includes five to 34 cytosine-thymine-guanine (CTG) repeats. The mutant version of the gene includes 50 to as many as 10,000 CTG repeats.

“The longer the repeat the worse the disease and the earlier the onset of the disease,” said U. of I. chemistry professor and department head Steven Zimmerman, who co-led the research with his colleague, chemistry professor Anne Baranger.

When the mutant DMPK is transcribed into RNA, the first step toward building a protein, these (now CUG) repeats bind to a cellular protein, MBNL, which normally splices other RNA transcripts. The bound MBNL cannot function properly, causing a cascade of negative effects in the cell. Improperly spliced RNAs lead to improperly formed proteins.

Preventing the MBNL protein from binding to the CUG repeats has been shown to ease the symptoms of the disease.

“The RNA is the primary target” for drug design, Zimmerman said. “It’s quite clear that if we can bind to the RNA and displace the protein, it’s very likely to relieve the symptoms.”

The CUG repeats in the aberrant RNA are an ideal target for drug development because they are not found in any other known RNA molecule, Baranger said.

“They don’t have a normal function, so it’s okay to bind to those repeats,” she said. “You certainly don’t want to target the protein because you want it to go perform its normal function.”

In the course of basic research into compounds that bind to DNA or RNA, the researchers designed a molecule that would selectively bind to T-T or U-U mismatches in DNA or RNA, respectively. (Mismatches occur when two nucleotides in a double-stranded molecule are improperly paired, as occurs in the CTG repeats in the mutant DNA and the CUG repeats in the RNA.) Their compound, which they call Ligand 1, binds to the region of excessive repeats in both the RNA and DNA from the aberrant DMPK gene. More importantly, Ligand 1 prevents the MBNL protein from binding to the RNA.

Further tests revealed that the new compound has significantly lower affinity for other mismatches in DNA or RNA. Baranger’s lab also tested the compound on other normal protein-RNA complexes, and found that it did not disrupt those interactions.

This last finding was critical, Zimmerman said.

“The danger is if you make something that binds to RNA or DNA, it’s going to bind to all these other molecules and disrupt those complexes, so you help one problem but you cause all these others. Our molecule doesn’t do that.”

Zimmerman and Baranger, with their colleague, chemistry professor Paul Hergenrother, are the recipients of a new five-year nearly $2 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health to pursue this research.

Diana Yates | University of Illinois
Further information:
http://www.illinois.edu

Further reports about: Baranger CTG DMPK DNA MBNL Molecule Pathology RNA Small Molecule dystrophy inhibits muscular dystrophy myotonic protein-RNA complexes

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>