Featured Research

from universities, journals, and other organizations

Scientists uncover most detailed picture yet of muscular dystrophy defect then design targeted new drug candidates

Date:
January 2, 2014
Source:
Scripps Research Institute
Summary:
Scientists have revealed an atomic-level view of a genetic defect that causes a form of muscular dystrophy, myotonic dystrophy type 2, and have used this information to design drug candidates with potential to counter those defects—and reverse the disease.

Scripps Florida scientists revealed a detailed image of the genetic defect that causes myotonic dystrophy type 2, then used that information to design a drug candidate to counteract the disease.
Credit: Image courtesy of Scripps Research Institute

Scientists from The Scripps Research Institute have revealed an atomic-level view of a genetic defect that causes a form of muscular dystrophy, myotonic dystrophy type 2, and have used this information to design drug candidates with potential to counter those defects -- and reverse the disease.

"This the first time the structure of the RNA defect that causes this disease has been determined," said TSRI Associate Professor Matthew Disney, who led the study. "Based on these results, we designed compounds that, even in small amounts, significantly improve disease-associated defects in treated cells."

Myotonic dystrophy type 2 is a relatively rare form of muscular dystrophy that is somewhat milder than myotonic dystrophy type 1, the most common adult-onset form of the disease.

Both types of myotonic dystrophy are inherited disorders that involve progressive muscle wasting and weakness, and both are caused by a type of genetic defect known as a "RNA repeat expansion," a series of nucleotides repeated more times than normal in an individual's genetic code. The repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities -- which lead to the disease.

Many other researchers had tried to find the atomic-level structure of the myotonic dystrophy 2 repeat, but had run into technical difficulties. In a technique called X-ray crystallography, which is used to find detailed structural information, scientists manipulate a molecule so that a crystal forms. This crystal is then placed in a beam of X-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of diffraction, scientists can then reconstruct the shape of the original molecule.

Prior to the new research, which was published in an advance, online issue of the journal ACS Chemical Biology, scientists had not been able to crystallize the problematic RNA. The Scripps Florida team spent several years on the problem and succeeded in engineering the RNA to have crystal contacts in different positions. This allowed the RNA to be crystallized -- and its structure to be revealed.

Using information about the RNA's structure and movement, the scientists were able to design molecules to improve RNA function.

The new findings were confirmed using sophisticated computational models that show precisely how the small molecules interact with and alter the RNA structure over time. Those predictive models matched what the scientists found in the study -- that these new compounds bind to the repeat structure in a predictable and easily reproducible way, attacking the cause of the disease.

"We used a bottom-up approach, by first understanding how the small components of the RNA structure interact with small molecules," said Jessica Childs-Disney of TSRI, who was first author of the paper with Ilyas Yildirim of Northwestern University. "The fact that our compounds improve the defects shows that our unconventional approach works."


Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Jessica L. Childs-Disney, Ilyas Yildirim, HaJeung Park, Jeremy R. Lohman, Lirui Guan, Tuan Tran, Partha Sarkar, George C. Schatz, Matthew D. Disney. Structure of the Myotonic Dystrophy Type 2 RNA and Designed Small Molecules That Reduce Toxicity. ACS Chemical Biology, 2013; 131216144058009 DOI: 10.1021/cb4007387

Cite This Page:

Scripps Research Institute. "Scientists uncover most detailed picture yet of muscular dystrophy defect then design targeted new drug candidates." ScienceDaily. ScienceDaily, 2 January 2014. <www.sciencedaily.com/releases/2014/01/140102133027.htm>.
Scripps Research Institute. (2014, January 2). Scientists uncover most detailed picture yet of muscular dystrophy defect then design targeted new drug candidates. ScienceDaily. Retrieved September 2, 2014 from www.sciencedaily.com/releases/2014/01/140102133027.htm
Scripps Research Institute. "Scientists uncover most detailed picture yet of muscular dystrophy defect then design targeted new drug candidates." ScienceDaily. www.sciencedaily.com/releases/2014/01/140102133027.htm (accessed September 2, 2014).

Share This




More Health & Medicine News

Tuesday, September 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

Newsy (Sep. 2, 2014) The U.N. says the problem is two-fold — quarantine zones and travel restrictions are limiting the movement of both people and food. Video provided by Newsy
Powered by NewsLook.com
Get on Your Bike! London Cycling Popularity Soars Despite Danger

Get on Your Bike! London Cycling Popularity Soars Despite Danger

AFP (Sep. 1, 2014) Wedged between buses, lorries and cars, cycling in London isn't for the faint hearted. Nevertheless the number of people choosing to bike in the British capital has doubled over the past 15 years. Duration: 02:27 Video provided by AFP
Powered by NewsLook.com
Can You Train Your Brain To Eat Healthy?

Can You Train Your Brain To Eat Healthy?

Newsy (Sep. 1, 2014) New research says if you condition yourself to eat healthy foods, eventually you'll crave them instead of junk food. Video provided by Newsy
Powered by NewsLook.com
We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins