Featured Research

from universities, journals, and other organizations

New compounds display strong therapeutic potential for cystic fibrosis

Date:
September 30, 2013
Source:
CNRS (Délégation Paris Michel-Ange)
Summary:
Cystic fibrosis is a lethal genetic disorder that in France affects one child per 4,500 births. An international team has recently discovered two new compounds that could be used to treat patients carrying the most common mutation. By means of virtual screening and experiments on mice and human cells in culture, the scientists were able to screen 200,000 compounds and selected two that allowed the causal mutated protein to express itself and fulfill its function.

Cystic fibrosis is a lethal genetic disorder that in France affects one child per 4,500 births. An international team led by scientists at the Institut Fédératif de Recherche Necker-Enfants Malades (CNRS/Inserm/Université Paris Descartes)[1], led by Aleksander Edelman, has recently discovered two new compounds that could be used to treat patients carrying the most common mutation. By means of virtual screening and experiments on mice and human cells in culture, the scientists were able to screen 200,000 compounds and selected two that allowed the causal mutated protein to express itself and fulfill its function. These findings were recently published online in EMBO Molecular Medicine.

Cystic fibrosis is a genetic disorder that affects the epithelia[2] of numerous organs, and particularly those in the lungs, pancreas and intestine. In the lungs, this takes the form of insufficient epithelial hydration, resulting in excess mucus in the bronchi. This mucus retains pathogenic agents and favors the onset of chronic infections and inflammatory conditions that are ultimately fatal to the sufferer.

The disease is caused by mutations in the gene coding for a protein called CFTR (cystic fibrosis transmembrane conductance regulator). This protein, which is essential to ensure the passage of water through an epithelium, is an ion channel that allows chloride ions to pass through cell membranes. To date, about 2,000 gene mutations that cause the disease have been determined, but 70% of cases of cystic fibrosis are due to a single mutation called ΔF508. And it is this mutation that is targeted by the recently-discovered compounds.

The scientists used computer techniques to screen 200,000 compounds, looking for those that might interact with a specific zone in the abnormal protein, and found about a dozen potentially active molecules. Using these 12 compounds, they then performed in-vitro tests on human cell cultures and in-vivo experiments on mice showing this mutation. They were thus able to observe that two of these compounds allowed the mutated ΔF508-CFTR protein to be trafficked to the membrane and fulfill its role.

One of the highlights of this work was that the scientists were able to describe the mechanism of action of these two compounds. In itself, and despite its mutation, the ΔF508-CFTR protein may satisfactorily fulfill its function. The problem is that once it is synthesized, it is recognized as being abnormal by keratin 8, another protein which favors its degradation, thus preventing ΔF508-CFTR from reaching the cell membrane. The compounds discovered by the scientists inhibit the interaction between keratin 8 and ΔF508-CFTR so that the protein can be deployed appropriately and fulfill its role as an ion channel. The scientists think that for potential therapeutic purposes, the two molecules they have discovered could be associated with "potentiating" compounds that would enhance the activity of ΔF508-CFTR.

The scientists now want to determine whether these two compounds do indeed cause a reduction in the susceptibility to infection of cystic fibrosis mice models. They also hope to start clinical trials in cystic fibrosis patients in the coming years.


Story Source:

The above story is based on materials provided by CNRS (Délégation Paris Michel-Ange). Note: Materials may be edited for content and length.


Journal Reference:

  1. Norbert Odolczyk, Janine Fritsch, Caroline Norez, Nathalie Servel, Melanie Faria da Cunha, Sara Bitam, Anna Kupniewska, Ludovic Wiszniewski, Julien Colas, Krzysztof Tarnowski, Danielle Tondelier, Ariel Roldan, Emilie L. Saussereau, Patricia Melin-Heschel, Grzegorz Wieczorek1, Gergely Lukacs, Michal Dadlez, Grazyna Faure, Harald Herrmann, Mario Ollero, Frédéric Becq, Piotr Zielenkiewicz, Aleksander Edelman. Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain. EMBO Molecular Medicine, September 2013

Cite This Page:

CNRS (Délégation Paris Michel-Ange). "New compounds display strong therapeutic potential for cystic fibrosis." ScienceDaily. ScienceDaily, 30 September 2013. <www.sciencedaily.com/releases/2013/09/130930093718.htm>.
CNRS (Délégation Paris Michel-Ange). (2013, September 30). New compounds display strong therapeutic potential for cystic fibrosis. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2013/09/130930093718.htm
CNRS (Délégation Paris Michel-Ange). "New compounds display strong therapeutic potential for cystic fibrosis." ScienceDaily. www.sciencedaily.com/releases/2013/09/130930093718.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) — New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) — Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com
Tooth Plaque Provides Insight Into Diets Of Ancient People

Tooth Plaque Provides Insight Into Diets Of Ancient People

Newsy (July 19, 2014) — Research on plaque from ancient teeth shows that our prehistoric ancestor's had a detailed understanding of plants long before developing agriculture. Video provided by Newsy
Powered by NewsLook.com
Contaminated Water Kills 3 Babies in South African Town

Contaminated Water Kills 3 Babies in South African Town

AFP (July 18, 2014) — Contaminated water in South Africa's northwestern town of Bloemhof kills three babies and hospitalises over 500 people. The incident highlights growing fears over water safety in South Africa. Duration: 02:22 Video provided by AFP
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