tailieunhanh - Báo cáo khoa hoc : Novel therapeutics based on recombinant botulinum neurotoxins to normalize the release of transmitters and pain mediators

A major unmet clinical need exists for long-acting neurotherapeutics to alleviate chronic pain in patients unresponsive to available nonaddictive analgesics. Herein, a new strategy is described for the development of potent and specific inhibitors of the neuronal exocytosis of transmitters and pain mediators that exhibit unique antinociceptive activity. | IFEBS Journal REVIEW ARTICLE Novel therapeutics based on recombinant botulinum neurotoxins to normalize the release of transmitters and pain mediators J. Oliver Dolly Jiafu Wang Tomas H. Zurawski and Jianghui Meng InternationalCentre for Neurotherapeutics Dublin City University Ireland Keywords antinociceptive neuroexocytosis sensory neurons SNAP-25 SNARE Correspondence J. Oliver Dolly InternationalCentre for Neurotherapeutics Dublin City University Glasnevin Dublin 9 Ireland Fax 353 1 700 7758 Tel 353 1 700 7757 E-mail Received 6 April 2011 revised 26 May 2011 accepted 3 June 2011 doi A major unmet clinical need exists for long-acting neurotherapeutics to alleviate chronic pain in patients unresponsive to available nonaddictive analgesics. Herein a new strategy is described for the development of potent and specific inhibitors of the neuronal exocytosis of transmitters and pain mediators that exhibit unique antinociceptive activity. This entailed recombinant production in Escherichia coli of two serotypes of botulinum neurotoxin BoNT BoNTA and BoNTE which are proteins that are known to block the release of transmitters by targeting and entering nerve endings where their proteases cleave and inactivate a protein synaptosomal protein of Mr 25 000 SNAP-25 that is essential for Ca2 -regulated exocytosis. Site-directed mutagenesis of Leu428 and Leu429 in BoNTA revealed that the remarkable longevity of its neuroparalytic action is attributable to a dileucine-containing motif. BoNTE acts transiently because it lacks these residues but is a superior inhibitor of transient receptor potential vanilloid type 1-mediated release of pain peptides from sensory nerves. The advantageous features of each serotype were harnessed by attaching the BoNTE protease moiety to an enzymically inactive mutant of BoNTA. The resultant purified composite protein could target motoneurons by binding to the BoNTA ectoacceptor and persistently .

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