Featured Research

from universities, journals, and other organizations

Drug Target For The Most Potent Botulinum Neurotoxin Determined

Date:
May 1, 2008
Source:
DOE/Brookhaven National Laboratory
Summary:
Botulinum neurotoxin -- responsible for the deadly food poisoning disease botulism and for the beneficial effects of smoothing out facial wrinkles - can also be used as a dreaded biological weapon. When ingested or inhaled, less than a billionth of an ounce can cause muscle paralysis and eventual death. Although experimental vaccines administered prior to exposure can inhibit the destructive action of this neurotoxin - the most deadly protein known to humans -- no effective pharmacological treatment exists. Scientists have now taken the first step toward designing an effective antidote to the most potent form of botulinum neurotoxin.

Reviewing their data are (from left) Brookhaven Lab researchers Subramanyam Swaminathan, Desigan Kumaran and Richa Rawat.
Credit: Image courtesy of DOE/Brookhaven National Laboratory

Botulinum neurotoxin -- responsible for the deadly food poisoning disease botulism and for the beneficial effects of smoothing out facial wrinkles - can also be used as a dreaded biological weapon. When ingested or inhaled, less than a billionth of an ounce can cause muscle paralysis and eventual death. Although experimental vaccines administered prior to exposure can inhibit the destructive action of this neurotoxin - the most deadly protein known to humans -- no effective pharmacological treatment exists.

Now, scientists at the U.S. Department of Energy's Brookhaven National Laboratory and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) have taken the first step toward designing an effective antidote to the most potent form of the toxin. They have found that they can trick the toxin to bypass its normal binding protein, thereby blocking its deadly action.

"We have found a highly efficient inhibitor of botulinum neurotoxin type A - the most potent of seven neurotoxins produced by the bacterium Clostridium botulinum. This finding can lead to a very effective drug to stop the devastating effects of the toxin," said Brookhaven Lab biologist Subramanyam Swaminathan, the study's co-principal investigator. "We intend to do further research to tailor the inhibitor for the best results."

"We are excited about the success of this work and the prospects it holds for future drug development," said USAMRIID principal investigator S. Ashraf Ahmed, who initiated the structure-based inhibitor design as part of the Institute's bio-defense research program.

To cause its deadly effects, the botulinum neurotoxin first binds to a nerve cell membrane, which curves inward, incorporating the toxin into a vesicle that drifts inside the cell. The toxin eventually travels from the vesicle to the cytosol, the internal fluid of the cell. The toxin then cleaves specific proteins in the cytosol, thereby blocking the release of neurotransmitters - chemicals nerve cells use to communicate with one another and with muscles. Blockage of this communication paralyzes muscles - including those that enable breathing.

To block the toxin's action, the researchers designed four "decoy" protein fragments that mimic the structure of the protein to which the toxin ordinarily binds. The toxin then attaches itself to the decoy fragments instead of to the cell's protein. This re-routing of the toxin allows neurotransmitters to keep functioning, thus stopping the toxin's pathological effects.

The scientists used x-ray techniques at Brookhaven's National Synchrotron Light Source (NSLS) to see how the toxin binds to the protein inhibitors. They found that all four decoy proteins are efficient at inhibiting the toxin's binding to the cell's protein, but one of them in particular is by far the best of any known inhibitors. The scientists' next step in this process is to transform the most effective of the four protein fragments into a drug-like molecule before clinical testing is done.

"This study represents an impressive collaboration in identifying potential inhibitors of the toxin for therapeutic use," said Colonel George W. Korch, Jr., USAMRIID's commander. "It builds upon the successes we have realized in developing effective next-generation vaccines to protect our citizens against the toxin's deadly effects prior to exposure."

The scientists did not work with intact Clostridium botulinum bacteria. Instead, they produced a functional fragment of the neurotoxin protein, which is not toxic. The research is performed in strict compliance with Brookhaven's Institutional Biosafety Committee regulations according to standards set by the U.S. Centers for Disease Control and Prevention. Only authorized scientists have access to the laboratory.

The results of their research are reported in the April 22, 2008 online issue of the Journal of Biological Chemistry. This research was funded by the Defense Threat Reduction Agency of the U.S. Department of Defense. The NSLS is supported by the U.S. Department of Energy's Office of Basic Energy Sciences, Office of Science.


Story Source:

The above story is based on materials provided by DOE/Brookhaven National Laboratory. Note: Materials may be edited for content and length.


Cite This Page:

DOE/Brookhaven National Laboratory. "Drug Target For The Most Potent Botulinum Neurotoxin Determined." ScienceDaily. ScienceDaily, 1 May 2008. <www.sciencedaily.com/releases/2008/04/080429102646.htm>.
DOE/Brookhaven National Laboratory. (2008, May 1). Drug Target For The Most Potent Botulinum Neurotoxin Determined. ScienceDaily. Retrieved August 2, 2014 from www.sciencedaily.com/releases/2008/04/080429102646.htm
DOE/Brookhaven National Laboratory. "Drug Target For The Most Potent Botulinum Neurotoxin Determined." ScienceDaily. www.sciencedaily.com/releases/2008/04/080429102646.htm (accessed August 2, 2014).

Share This




More Plants & Animals News

Saturday, August 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Pyrenees Orphan Bear Cub Gets Brand New Home

Pyrenees Orphan Bear Cub Gets Brand New Home

AFP (Aug. 1, 2014) The discovery of a bear cub in the Pyrenees mountains made headlines in April 2014. Despire several attempts to find the animal's mother, the cub remained alone. Now, the Pyrenees Conservation Foundation has constructed an enclosure. Duration: 00:31 Video provided by AFP
Powered by NewsLook.com
Ebola Vaccine Might Be Coming, But Where's It Been?

Ebola Vaccine Might Be Coming, But Where's It Been?

Newsy (Aug. 1, 2014) Health officials are working to fast-track a vaccine — the West-African Ebola outbreak has killed more than 700. But why didn't we already have one? Video provided by Newsy
Powered by NewsLook.com
Study Links Certain Birth Control Pills To Breast Cancer

Study Links Certain Birth Control Pills To Breast Cancer

Newsy (Aug. 1, 2014) Previous studies have made the link between birth control and breast cancer, but the latest makes the link to high-estrogen oral contraceptives. Video provided by Newsy
Powered by NewsLook.com
Rare Whale Fossil Pulled from Calif. Backyard

Rare Whale Fossil Pulled from Calif. Backyard

AP (Aug. 1, 2014) A rare whale fossil has been pulled from a Southern California backyard. The 16- to 17-million-year-old baleen whale fossil is one of about 20 baleen whale fossils known to exist. (Aug. 1) Video provided by AP
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