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 Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

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: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>