Exploitation of Botulinum Neurotoxins for Research and Clinical Purposes

Abstract

The major long-term goal of this contract is to develop a novel and effective treatment for human botulism by producing a drug, capable of neutralising the intracellular neuroparalytical action of botulinum neurotoxin (BoNT), and delivering this inside cholinergic neurons via a innocuous transporter form of the toxins. Towards this end, our multi-disciplinary research has demonstrated that BoNTs target to murine motor nerve endings by interaction with distinct ecto-acceptors uniquely located thereon; this 'productive' binding requires a conformation of the toxin's heavy chain (HC) that is maintained by its 'natural' association with the light chain (LC), even in the absence of the inter-chain disulphide. The subsequent acceptor-mediated uptake step could be monitored by high-resolution electron-microscopy of motor endplates labelled with BoNT-gold-conjugate, and from measurement of the inhibition of transmitter release produced by the resultant internalised LC. Importantly, experiments with modified forms of BoNT and its constituent chains revealed that the inter-chain S-S bond or its half-cyst-ines are essential for neuronal membrane translocation whereas neither the latter nor any of the toxin's free cysteines are necessary for intracellular blockade of transmitter release; in fact, alkylation of LC did not alter its ability to block acetylcholine release when administered intraneuronally.... Botulism, Botulinum neurotoxins, Tetanus toxin, Ectoacceptors for clostridial toxins, Neuronal internalisation of botulinum neurotoxins, Exocytosis, Neurotransmitter release, Monoclonal antibodies to botulinum neurotoxin, Chromaffin cells, Pancreatic acini, Synaptobrevin, Neutral metalloproteases, Inhibitors of Zn2+-dependent proteases, Cholinergic targetted transporter.

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Document Details

Document Type
Technical Report
Publication Date
Jun 01, 1993
Accession Number
ADA267127

Entities

People

  • J. O. Dolly

Organizations

  • Imperial College London

Tags

DTIC Thesaurus Topics

  • Amines
  • Amino Acids
  • Body Fluids
  • Cell Membrane
  • Cell Physiological Processes
  • Cells
  • Chemistry
  • Cholinergic Nerves
  • Dermatologic Agents
  • Endocrine Cells
  • Enzyme Inhibitors
  • Measurement
  • Neurons
  • Peripheral Nervous System
  • Rodents
  • Synapses

Fields of Study

  • Biology

Readers

  • Microbial Pathology
  • Molecular and Cellular Biochemistry

Technology Areas

  • Microelectronics