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 Scientists find new approach that shows promise for treating cystic fibrosis
14.03.2019 | NIH/National Heart, Lung and Blood Institute

nachricht Lab grown ‘brains’ successfully model disease
13.03.2019 | Max-Planck-Institut für Psychiatrie

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: Revealing the secret of the vacuum for the first time

New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum

For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...

Im Focus: Sussex scientists one step closer to a clock that could replace GPS and Galileo

Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock

Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...

Im Focus: Sensing shakes

A new way to sense earthquakes could help improve early warning systems

Every year earthquakes worldwide claim hundreds or even thousands of lives. Forewarning allows people to head for safety and a matter of seconds could spell...

Im Focus: A thermo-sensor for magnetic bits

New concept for energy-efficient data processing technology

Scientists of the Department of Physics at the University of Hamburg, Germany, detected the magnetic states of atoms on a surface using only heat. The...

Im Focus: The moiré patterns of three layers change the electronic properties of graphene

Combining an atomically thin graphene and a boron nitride layer at a slightly rotated angle changes their electrical properties. Physicists at the University of Basel have now shown for the first time the combination with a third layer can result in new material properties also in a three-layer sandwich of carbon and boron nitride. This significantly increases the number of potential synthetic materials, report the researchers in the scientific journal Nano Letters.

Last year, researchers in the US caused a big stir when they showed that rotating two stacked graphene layers by a “magical” angle of 1.1 degrees turns...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Modelica Conference with 330 visitors from 21 countries at OTH Regensburg

11.03.2019 | Event News

Selection Completed: 580 Young Scientists from 88 Countries at the Lindau Nobel Laureate Meeting

01.03.2019 | Event News

LightMAT 2019 – 3rd International Conference on Light Materials – Science and Technology

28.02.2019 | Event News

 
Latest News

Researchers measure near-perfect performance in low-cost semiconductors

18.03.2019 | Power and Electrical Engineering

Nanocrystal 'factory' could revolutionize quantum dot manufacturing

18.03.2019 | Materials Sciences

Long-distance quantum information exchange -- success at the nanoscale

18.03.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>