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rdf:type |
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lifeskim:mentions |
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pubmed:dateCreated |
2004-3-17
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pubmed:abstractText |
Clostridial neurotoxins potently and specifically inhibit neurotransmitter release in defined cell types. Previously reported data have demonstrated that the catalytically active LH(N) endopeptidase fragment of botulinum neurotoxin type A (termed LH(N)/A) can be retargeted to a range of cell types in vitro to lead to inhibition of secretion of a range of transmitters. Here, we report the synthesis of endopeptidase conjugates with in vitro selectivity for nociceptive afferents compared to spinal neurons. Chemical conjugates prepared between Erythrina cristagalli lectin and LH(N)/A are assessed in vitro and in in vivo models of pain. Chemical conjugates prepared between E. cristagalli lectin and either natively sourced LH(N)/A, or recombinant LH(N)/A purified from Escherichia coli are assessed, and equivalence of the recombinant material is demonstrated. The duration of action of inhibition of neurotransmitter release by the conjugate in vitro is also assessed and is comparable to that observed with Clostridium botulinum neurotoxin. Selectivity of targeting and therapeutic potential have been confirmed by in vivo electrophysiology studies. Furthermore, the analgesic properties of the conjugate have been assessed in in vivo models of pain and extended duration effects observed. These data provide proof of principle for the concept of retargeted clostridial endopeptidases as novel analgesics.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Botulinum Toxins, Type A,
http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Immunotoxins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Neuromuscular Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Neurotransmitter Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Snap25 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Substance P,
http://linkedlifedata.com/resource/pubmed/chemical/Synaptosomal-Associated Protein 25
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0885-3185
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pubmed:author |
pubmed-author:AlexanderFrances C GFC,
pubmed-author:ChaddockJohn AJA,
pubmed-author:DickensonAnthonyA,
pubmed-author:DowardSarahS,
pubmed-author:DugganMichael JMJ,
pubmed-author:FooksSarah JSJ,
pubmed-author:FosterKeith AKA,
pubmed-author:FriisLorna MLM,
pubmed-author:GreenG MarkGM,
pubmed-author:HallYper H JYH,
pubmed-author:KirbyElizabeth RER,
pubmed-author:LeedsNicolaN,
pubmed-author:MoulsdaleHilary JHJ,
pubmed-author:PurkissJohn RJR,
pubmed-author:QuinnConrad PCP,
pubmed-author:RahmanWahidaW,
pubmed-author:ShoneClifford CCC,
pubmed-author:SuzukiRieR
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pubmed:copyrightInfo |
Copyright 2004 Movement Disorder Society
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pubmed:issnType |
Print
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pubmed:volume |
19 Suppl 8
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
S42-7
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15027053-Action Potentials,
pubmed-meshheading:15027053-Animals,
pubmed-meshheading:15027053-Botulinum Toxins, Type A,
pubmed-meshheading:15027053-Cells, Cultured,
pubmed-meshheading:15027053-Disease Models, Animal,
pubmed-meshheading:15027053-Dose-Response Relationship, Drug,
pubmed-meshheading:15027053-Embryo, Mammalian,
pubmed-meshheading:15027053-Endopeptidases,
pubmed-meshheading:15027053-Ganglia, Spinal,
pubmed-meshheading:15027053-Glycine,
pubmed-meshheading:15027053-Immunotoxins,
pubmed-meshheading:15027053-Membrane Proteins,
pubmed-meshheading:15027053-Mice,
pubmed-meshheading:15027053-Nerve Fibers, Unmyelinated,
pubmed-meshheading:15027053-Nerve Tissue Proteins,
pubmed-meshheading:15027053-Neuromuscular Agents,
pubmed-meshheading:15027053-Neurons,
pubmed-meshheading:15027053-Neurotransmitter Agents,
pubmed-meshheading:15027053-Pain,
pubmed-meshheading:15027053-Pain Measurement,
pubmed-meshheading:15027053-Reaction Time,
pubmed-meshheading:15027053-Spinal Cord,
pubmed-meshheading:15027053-Substance P,
pubmed-meshheading:15027053-Synaptic Transmission,
pubmed-meshheading:15027053-Synaptosomal-Associated Protein 25,
pubmed-meshheading:15027053-Time Factors
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pubmed:year |
2004
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pubmed:articleTitle |
Retargeted clostridial endopeptidases: inhibition of nociceptive neurotransmitter release in vitro, and antinociceptive activity in in vivo models of pain.
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pubmed:affiliation |
Health Protection Agency, Porton Down, Salisbury, Wiltshire, United Kingdom. john.chaddock@hpa.org.uk
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pubmed:publicationType |
Journal Article,
Comparative Study,
In Vitro,
Research Support, Non-U.S. Gov't
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