Accession Number : ADA267127


Title :   Exploitation of Botulinum Neurotoxins for Research and Clinical Purposes


Descriptive Note : Midterm rept. 1 Aug 1991-30 Apr 1993


Corporate Author : IMPERIAL COLL OF SCIENCE AND TECHNOLOGYLONDON (UNITED KINGDOM) DEPT OF BIOCHEMISTRY


Personal Author(s) : Dolly, J O


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a267127.pdf


Report Date : Jun 1993


Pagination or Media Count : 59


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.


Descriptors :   *THERAPY , *CLOSTRIDIUM BOTULINUM , *NEUROTOXINS , MEASUREMENT , MEMBRANES(BIOLOGY) , HUMANS , INTERACTIONS , PROTEINS , RESOLUTION , HIGH RESOLUTION , ELECTRON MICROSCOPY , TRANSMITTERS , NERVE CELLS , ALKYLATION , GENES , INHIBITORS , MONOCLONAL ANTIBODIES , DRUGS , INHIBITION , NEUROTRANSMITTERS , PHARMACOLOGICAL ANTAGONISTS , GOLD COMPOUNDS , PEPTIDE HYDROLASES , ACETYLCHOLINE , TETANUS , TRANSLOCATION , CYSTS , UNITED KINGDOM


Subject Categories : Medicine and Medical Research
      Toxicology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE