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Exchanging the minimal cell binding fragments of tetanus neurotoxin in botulinum neurotoxin A and B impacts their toxicity at the neuromuscular junction and central neurons.
- Source :
-
Toxicon : official journal of the International Society on Toxinology [Toxicon] 2013 Dec 01; Vol. 75, pp. 108-21. Date of Electronic Publication: 2013 Jun 29. - Publication Year :
- 2013
-
Abstract
- The modular four domain structure of clostridial neurotoxins supports the idea to reassemble individual domains from tetanus and botulinum neurotoxins to generate novel molecules with altered pharmacological properties. To treat disorders of the central nervous system drug transporter molecules based on catalytically inactive clostridial neurotoxins circumventing the passage of the blood-brain-barrier are desired. Such molecules can be produced based on the highly effective botulinum neurotoxin serotype A incorporating the retrograde axonal sorting property of tetanus neurotoxin which is supposed to be encoded within its C-terminal cell binding domain HC. The corresponding exchange of the tetanus neurotoxin HC-fragment in botulinum neurotoxin A yielded the novel hybrid molecule AATT which displayed decreased potency at the neuromuscular junction like tetanus neurotoxin but exerted equal activity in cortical neurons compared to botulinum neurotoxin A wild-type. Minimizing the tetanus neurotoxin cell binding domain to its N- or C-terminal half drastically reduced the potencies of AATA and AAAT in cortical neurons indicating that the structural motif mediating sorting of tetanus neurotoxin is predominantly encoded within the entire HC-fragment. However, the reciprocal exchange resulted in TTAA which showed a similar potency as tetanus neurotoxin at the neuromuscular junction indicating that the tetanus neurotoxin portion prevents a high potency as observed for botulinum neurotoxins. In conclusion, clostridial neurotoxin based inactivated drug transporter for targeting central neurons should contain the cell binding domain of tetanus neurotoxin to exert its tropism for the central nervous system.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cell Membrane drug effects
Cell Membrane metabolism
Circular Dichroism
Escherichia coli metabolism
Hippocampus drug effects
Hippocampus metabolism
Mice
Neuromuscular Junction metabolism
Neurons metabolism
Protein Binding
Protein Transport
Recombinant Proteins genetics
Recombinant Proteins metabolism
Botulinum Toxins toxicity
Botulinum Toxins, Type A toxicity
Metalloendopeptidases toxicity
Neuromuscular Junction drug effects
Neurons drug effects
Tetanus Toxin toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3150
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- Toxicon : official journal of the International Society on Toxinology
- Publication Type :
- Academic Journal
- Accession number :
- 23817019
- Full Text :
- https://doi.org/10.1016/j.toxicon.2013.06.010