Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Small-molecule inhibitors of botulinum neurotoxin identified

14.11.2003


Findings hold promise for developing new botulism therapies



Scientists have identified several key molecules that block the activity of a toxin that causes botulism--an important first step in developing therapeutics to counter the disease.

Botulinum neurotoxins (BoNT) are useful as therapeutic agents for treating a wide variety of muscle dysfunctions in humans, and are used cosmetically to reduce wrinkles. Paradoxically, the seven serotypes of BoNT, designated A through G, also are among the most lethal biological substances known.


Botulinum neurotoxins are composed of two peptide chains, a heavy chain (HC) and a light chain (LC). The heavy chain targets and binds to surface receptors on nerve terminals. The toxins are then internalized into the nerve terminal. Once inside, the light chain separates from the heavy chain and cleaves, or cuts, specific proteins that control neuromuscular function. Cleavage of these proteins effectively blocks the release of neurotransmitters that cause the muscle contractions necessary for respiration. The result is a flaccid paralysis that ultimately leads to suffocation and death.

Because botulinum neurotoxins are capable of causing mass casualties, they are classified as biodefense A (top priority) agents by the Centers for Disease Control and Prevention. Currently, no therapeutics exist to counter the threat; thus, identifying and developing compounds that inhibit the neurotoxins is a high priority.

In an article published last month in Biochemical and Biophysical Research Communications, and recently highlighted in Nature Reviews in Drug Discovery, investigators from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), the National Cancer Institute (NCI), and the University of Nebraska Medical Center (UNMC) report using a high-throughput assay to screen a group of 1,990 compounds known as the NCI diversity set. The molecular properties of this group are predictive of a larger set of more than 100,000 compounds.

Using a two-stage assay, the team identified a number of compounds that inhibited the enzymatic action of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified by high-performance liquid chromatography. Finally, molecular modeling techniques were used to predict structural features that contribute to inhibitor binding and potency.

These techniques revealed a common pharmacophore--a "scaffold" upon which future therapeutics can be built. This pharmacophore will serve as a basis for directing future efforts to develop BoNT/A LC inhibitors with enhanced potency. Testing in cell culture will be followed by animal modeling once the most promising candidates have been identified.

Study collaborators were Sina Bavari, James J. Schmidt, and Robert G. Stafford of USAMRIID; Rick Gussio, Daniel W. Zaharevitz, Edward A. Sausville, Douglas J. Lane, Connor F. McGrath, Ann R. Hermone, Tam L. Nguyen, Rekha G. Panchal, and James C. Burnett of NCI; and Jonathan L. Vennerstrom of UNMC.

"This work is the result of a productive collaboration between federal and academic partners," said Colonel Erik A. Henchal, commander of USAMRIID. "These are the relationships that will, in the future, deliver the biodefense products the nation needs."


USAMRIID, located at Fort Detrick, Maryland, is the lead laboratory for the Medical Biological Defense Research Program, and plays a key role in national defense and in infectious disease research. The Institute’s mission is to conduct basic and applied research on biological threats resulting in medical solutions (such as vaccines, drugs and diagnostics) to protect the warfighter. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command.

Caree Vander Linden | EurekAlert!
Further information:
http://www.usamriid.army.mil/

More articles from Health and Medicine:

nachricht Serious children’s infections also spreading in Switzerland
26.07.2017 | Universitätsspital Bern

nachricht New vaccine production could improve flu shot accuracy
25.07.2017 | Duke University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Carbon Nanotubes Turn Electrical Current into Light-emitting Quasi-particles

Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers

Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...

Im Focus: Flexible proximity sensor creates smart surfaces

Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.

At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...

Im Focus: 3-D scanning with water

3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects

A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

 
Latest News

CCNY physicists master unexplored electron property

26.07.2017 | Physics and Astronomy

Molecular microscopy illuminates molecular motor motion

26.07.2017 | Life Sciences

Large-Mouthed Fish Was Top Predator After Mass Extinction

26.07.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>