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Future Developments: Engineering the Neurotoxin

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Clinical Applications of Botulinum Neurotoxin

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 5))

Abstract

Understanding the structure and molecular basis of neurotoxin function has opened up opportunities to engineer novel therapeutic proteins that utilise the neurotoxins and neurotoxin domains. These opportunities and the status of their development are reviewed in this chapter, which brings together the findings detailed in the companion volume to this book, KA Foster (ed) Molecular Aspects of Botulinum Neurotoxin, Springer, New York, and shows how they can be applied for the development of innovative therapeutics and research tools.

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References

  1. Bade S, Rummel A, Reisinger C, Karnath T, Ahnert-Hilger G, Bigalke H, Binz T (2004) Botulinum neurotoxin type D enables cytosolic delivery of enzymatically active cargo proteins to neurones via unfolded translocation intermediates. J Neurochem 91(6):1461–1472

    Article  CAS  PubMed  Google Scholar 

  2. Box M, Parks DA, Knight A, Hale C, Fishman PS, Fairweather NF (2003) A multi-domain protein system based on the HC fragment of tetanus toxin for targeting DNA to neuronal cells. J Drug Target 11(6):333–343

    Article  CAS  PubMed  Google Scholar 

  3. Carter AT, Paul CJ, Mason DR, Twine SM, Alston MJ, Logan SM, Austin JW, Peck MW (2009) Independent evolution of neurotoxin and flagellar genetic loci in proteolytic Clostridium botulinum. BMC Genomics 10:115

    Article  PubMed Central  PubMed  Google Scholar 

  4. Chaddock JA, Acharya KR (2011) Engineering toxins for 21st century therapies. FEBS J 278(6):899–904

    Article  CAS  PubMed  Google Scholar 

  5. Chaddock JA, Purkiss JR, Duggan MJ, Quinn CP, Shone CC, Foster KA (2000a) A conjugate composed of nerve growth factor coupled to a non-toxic derivative of Clostridium botulinum neurotoxin type A can inhibit neurotransmitter release in vitro. Growth Factors 18(2):147–155

    Article  CAS  Google Scholar 

  6. Chaddock JA, Purkiss JR, Friis LM, Broadbridge JD, Duggan MJ, Fooks SJ, Shone CC, Quinn CP, Foster KA (2000b) Inhibition of vesicular secretion in both neuronal and nonneuronal cells by a retargeted endopeptidase derivative of Clostridium botulinum neurotoxin type A. Infect Immun 68(5):2587–2593

    Article  CAS  Google Scholar 

  7. Chaddock JA, Herbert MH, Ling RJ, Alexander FCG, Fooks SJ, Revell DF, Quinn CP, Shone CC, Foster KA (2002) Expression and purification of catalytically active, non-toxic endopeptidase derivatives of Clostridium botulinum toxin type A. Protein Expr Purif 25:219–228

    Article  CAS  PubMed  Google Scholar 

  8. Chaddock JA, Purkiss JR, Alexander FC, Doward S, Fooks SJ, Friis LM, Hall YH, Kirby ER, Leeds N, Moulsdale HJ, Dickenson A, Green GM, Rahman W, Suzuki R, Duggan MJ, Quinn CP, Shone CC, Foster KA (2004) Retargeted clostridial endopeptidases: inhibition of nociceptive neurotransmitter release in vitro, and antinociceptive activity in in vivo models of pain. Mov Disord 19(Suppl 8):42–47

    Article  Google Scholar 

  9. Chen S, Barbieri JT (2009) Engineering botulinum neurotoxin to extend therapeutic intervention. Proc Natl Acad Sci U S A 106(23):9180–9184

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Darios F, Niranjan D, Ferrari E, Zhang F, Soloviev M, Rummel A, Bigalke H, Suckling J, Ushkaryov Y, Naumenko N, Shakirzyanova A, Giniatullin R, Maywood E, Hastings M, Binz T, Davletov B (2010) SNARE tagging allows stepwise assembly of a multimodular medicinal toxin. Proc Natl Acad Sci U S A 107(42):18197–18201

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Dolly JO, Wang J, Zurawski TH, Meng J (2011) Novel therapeutics based on recombinant botulinum neurotoxins to normalize the release of transmitters and pain mediators. FEBS J 278(23):4454–4466

    Article  CAS  PubMed  Google Scholar 

  12. Duggan MJ, Quinn CP, Chaddock JA, Purkiss JR, Alexander FC, Doward S, Fooks SJ, Friis LM, Hall YH, Kirby ER, Leeds N, Moulsdale HJ, Dickenson A, Green GM, Rahman W, Suzuki R, Shone CC, Foster KA (2002) Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. J Biol Chem 277(38):34846–34852

    Article  CAS  PubMed  Google Scholar 

  13. Erbguth FJ (2004) Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord 19(Suppl 8):2–6

    Article  Google Scholar 

  14. Ferrari E, Maywood ES, Restani L, Caleo M, Pirazzini M, Rossetto O, Hastings MH, Niranjan D, Schiavo G, Davletov B (2011) Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity. Toxins 3(4):345–355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Foster KA, Chaddock JA (2010) Targeted secretion inhibitors—innovative protein therapeutics. Toxins 2(12):2795–2815

    Article  CAS  PubMed Central  Google Scholar 

  16. Foster KA, Adams EJ, Durose L, Cruttwell CJ, Marks E, Shone CC, Chaddock JA, Cox CL, Heaton C, Sutton JM, Wayne J, Alexander FC, Rogers DF (2006) Re-engineering the target specificity of Clostridial neurotoxins—a route to novel therapeutics. Neurotox Res 9(2–3):101–107

    CAS  PubMed  Google Scholar 

  17. Henkel JS, Jacobson M, Tepp W, Pier C, Johnson Ea, Barbieri JT (2009) Catalytic properties of botulinum neurotoxin subtypes A3 and A4. Biochemistry 48:2522–2528

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Kumaran D, Eswaramoorthy S, Furey W, Navaza J, Sax M, Swaminathan S (2009) Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation. J Mol Biol 386:233–245

    Google Scholar 

  19. Kuo CL, Oyler GA, Shoemaker CB (2011) Accelerated neuronal cell recovery from botulinum neurotoxin intoxication by targeted ubiquitination. PLoS One 6(5):e20352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol 5(10):898–902

    Article  CAS  PubMed  Google Scholar 

  21. Masuyer G, Thiyagarajan N, James PL, Marks PM, Chaddock JA, Acharya KR (2009) Crystal structure of a catalytically active, non-toxic endopeptidase derivative of Clostridium botulinum toxin A. Biochem Biophys Res Commun 381(1):50–53

    Article  CAS  PubMed  Google Scholar 

  22. Masuyer G, Beard M, Cadd VA, Chaddock JA, Acharya KR (2011) Structure and activity of a functional derivative of Clostridium botulinum neurotoxin B. J Struct Biol 174(1):52–57

    Article  CAS  PubMed  Google Scholar 

  23. Pickett A, Perrow K (2011) Towards new uses of botulinum toxin as a novel therapeutic tool. Toxins 3:63–81

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Pier CL, Chen C, Tepp WH, Lin G, Janda KD, Barbieri JT, Pellett S, Johnson EA (2011) Botulinum neurotoxin subtype A2 enters neuronal cells faster than subtype A1. FEBS Lett 585(1):199–206

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Rummel A, Mahrhold S, Bigalke H, Binz T (2004) The HCC-domain of botulinum neurotoxins A and B exhibits a singular ganglioside binding site displaying serotype specific carbohydrate interaction. Mol Microbiol 51(3):631–643

    Article  CAS  PubMed  Google Scholar 

  26. Rummel A, Mahrhold S, Bigalke H, Binz T (2011) Exchange of the H(CC) domain mediating the double receptor recognition improves the pharmacodynamic properties of botulinum neurotoxin. FEBS J 278(23):4506–4515

    Article  CAS  PubMed  Google Scholar 

  27. Scott AB (1980) Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus 17(1):21–25

    CAS  PubMed  Google Scholar 

  28. Somm E, Bonnet N, Martinez A, Marks PM, Cadd VA, Elliott M, Toulotte A, Ferrari SL, Rizzoli R, Hüppi PS, Harper E, Melmed S, Jones R, Aubert ML (2012) A botulinum toxin-derived targeted secretion inhibitor downregulates the GH/IGF1 axis. J Clin Invest 122(9):3295–3306

    Article  PubMed Central  PubMed  Google Scholar 

  29. Sutton JM, Wayne J, Scott-tucker A, Brien SMO, Marks PMH, Alexander FCG, Shone CC, Chaddock JA (2005) Preparation of specifcally activatable endopeptidase derivatives of Clostridium botulinum toxins type A, B, and C and their applications. 40:31–41

    Google Scholar 

  30. Swaminathan S, Eswaramoorthy S (2000) Crystallization and preliminary X-ray analysis of Clostridium botulinum neurotoxin type B. Acta Crystallogr D Biol Crystallogr 56(Pt 8):1024–1026

    Article  CAS  PubMed  Google Scholar 

  31. Wang D, Zhang Z, Dong M, Sun S, Chapman ER, Jackson MB (2011) Syntaxin requirement for Ca2+-triggered exocytosis in neurons and endocrine cells demonstrated with an engineered neurotoxin. Biochemistry 50(14):2711–2713

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Wang J, Meng J, Lawrence GW, Zurawski TH, Sasse A, Bodeker MO, Gilmore MA, Fernandez-Salas E, Francis J, Steward LE, Aoki KR, Dolly JO (2008) Novel chimeras of botulinum neurotoxins A and E unveil contributions from the binding, translocation, and protease domains to their functional characteristics. J Biol Chem 283(25):16993–17002

    Article  CAS  PubMed  Google Scholar 

  33. Wang J, Zurawski TH, Meng J, Lawrence G, Olango WM, Finn DP, Wheeler L, Dolly JO (2011) A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. J Biol Chem 286(8):6375–6385

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Weller U, Dauzenroth ME, Gansel M, Dreyer F (1991) Cooperative action of the light chain of tetanus toxin and the heavy chain of botulinum toxin type A on the transmitter release of mammalian motor endplates. Neurosci Lett 122(1):132–134

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Syntaxin Ltd., Abingdon, UK

    John Chaddock

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  1. John Chaddock
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Correspondence to John Chaddock .

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

    Keith A. Foster

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Chaddock, J. (2014). Future Developments: Engineering the Neurotoxin. In: Foster, K. (eds) Clinical Applications of Botulinum Neurotoxin. Current Topics in Neurotoxicity, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0261-3_7

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