Various human neurogenic hyper-excitability disorders are successfully treated with type A or B BoNT (botulinum neurotoxin). The BoNT/A complex is widely used because of its longer-lasting benefits; also, autonomic side-effects are more often reported for BoNT/B. To establish if this distinct effect of BoNT/B could be exploited therapeutically, BoNT/A was modified so that it would bind the more abundant BoNT/B acceptor in rodents while retaining its desirable persistent action. The advantageous protease and translocation domain of BoNT/A were recombinantly combined with the acceptor-binding moiety of type B [HC/B (C-terminal half of BoNT/B heavy chain)], creating the chimaera AB. This purified protein bound the BoNT/B acceptor, displayed enhanced capability relative to type A for intraneuronally delivering its protease, cleaved SNAP-25 (synaptosome-associated protein of 25 kDa) and induced a more prolonged neuromuscular paralysis than BoNT/A in mice. The BA chimaera, generated by substituting HC/A (C-terminal half of BoNT/A heavy chain) into BoNT/B, exhibited an extremely high specific activity, delivered the BoNT/B protease via the BoNT/A acceptor into neurons, or fibroblast-like synoviocytes that lack SNAP-25, cleaving the requisite isoforms of VAMP (vesicle-associated membrane protein). Both chimaeras inhibited neurotransmission in murine bladder smooth muscle. BA has the unique ability to reduce exocytosis from non-neuronal cells expressing the BoNT/A-acceptor and utilising VAMP, but not SNAP-25, in exocytosis.
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May 2012
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Research Article|
April 26 2012
Longer-acting and highly potent chimaeric inhibitors of excessive exocytosis created with domains from botulinum neurotoxin A and B
Jiafu Wang
;
Jiafu Wang
*International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Tomas H. Zurawski
;
Tomas H. Zurawski
*International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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MacDara O. Bodeker
;
MacDara O. Bodeker
*International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Jianghui Meng
;
Jianghui Meng
*International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Sanjay Boddul
;
Sanjay Boddul
*International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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K. Roger Aoki
;
K. Roger Aoki
†Allergan, P.O. Box 19534, Irvine, CA 9262, U.S.A.
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J. Oliver Dolly
J. Oliver Dolly
1
*International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
1To whom correspondence should be addressed (email oliver.dolly@dcu.ie).
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Biochem J (2012) 444 (1): 59–67.
Article history
Received:
January 16 2012
Revision Received:
February 22 2012
Accepted:
February 23 2012
Accepted Manuscript online:
February 23 2012
Citation
Jiafu Wang, Tomas H. Zurawski, MacDara O. Bodeker, Jianghui Meng, Sanjay Boddul, K. Roger Aoki, J. Oliver Dolly; Longer-acting and highly potent chimaeric inhibitors of excessive exocytosis created with domains from botulinum neurotoxin A and B. Biochem J 15 May 2012; 444 (1): 59–67. doi: https://doi.org/10.1042/BJ20120100
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