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Pharmacology of Botulinum Neurotoxins: Exploitation of Their Multifunctional Activities as Transmitter Release Inhibitors and Neuron-Targeted Delivery Vehicles

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Molecular Aspects of Botulinum Neurotoxin

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 4))

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Abstract

Quantal transmitter release from nerves is inhibited by all seven serotypes (A–G) of botulinum neurotoxin (BoNT), with some subtle but functional differences. Commonalities and dissimilarities in these proteins, and new recombinant forms, are highlighted in terms of their multiple activities and domains responsible for binding to the neuronal acceptors, subsequent endocytosis, translocation and proteolytic inactivation of intracellular soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) culminating in the blockade of neuro-exocytosis lasting for weeks or months. The neurotoxins bind to dual acceptors, gangliosides and intra-lumenal regions of vesicular proteins, and co-traffic into neurons. Subsequently, their proteases pass to the cytosol via a channel created in the endosomal limiting membrane and cleave distinct bonds in the substrate SNARE(s). Modification of these targets is responsible for their characteristic pharmacological activities. The prolonged duration of type A seems attributable to an identified stabilisation motif that extends the longevity of its protease. BoNTs have proved instrumental in deciphering a molecular basis for regulated exocytosis; now, emerging knowledge is helping to explain why synchronisation of released quanta of transmitter is perturbed by certain serotypes (/B, /D and /F) and not others (/A, /C1 and /E). Novel chimeras created by protein engineering are endowed with advantageous features of two serotypes for targeting sensory neurons and alleviating inflammatory pain (LC/E-BoTIM/A). Likewise, an innocuous mutant of /B (BoTIM/B) fused to core streptavidin (CS-BoTIM/B) has been exploited for guiding molecular cargo and viral vectors into nerve cells. These novel discoveries exemplify the versatility of BoNT in targeting and delivering therapeutics into neurons.

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Acknowledgements

This research was supported by a Principal Investigator grant (to J.O.D.) from Science Foundation Ireland, a contract for basic research from Allergan Inc., a HDTRA contract (no. 1-07-C-0034) from the US Government, a commercialisation award from Enterprise Ireland, and funding under the Programme for Research in Third Level Institutions (PRTLI) Cycle 4. The PRTLI is co-funded through the European Regional Development Fund (ERDF), part of the European Union Structural Funds Programme 2007–2013. Group members (Drs. J. Wang, J. Meng and T. Zurawski) are thanked for their data cited in this review.

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  1. International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland

    J. O. Dolly, V. B. O’Leary & G. W. Lawrence

  2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ludwig-Maximilians-Universität München, München, Germany

    S. V. Ovsepian

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  1. J. O. Dolly
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  2. V. B. O’Leary
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  3. G. W. Lawrence
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  4. S. V. Ovsepian
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Correspondence to S. V. Ovsepian .

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  1. Units 4-10, Syntaxin Ltd., Abingdon, Oxfordshire, United Kingdom

    Keith A. Foster

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Dolly, J., O’Leary, V., Lawrence, G., Ovsepian, S. (2014). Pharmacology of Botulinum Neurotoxins: Exploitation of Their Multifunctional Activities as Transmitter Release Inhibitors and Neuron-Targeted Delivery Vehicles. In: Foster, K. (eds) Molecular Aspects of Botulinum Neurotoxin. Current Topics in Neurotoxicity, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9454-6_2

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