Engineered botulinum neurotoxins as new therapeutics

Geoffrey Masuyer, John A. Chaddock, Keith A. Foster, K. Ravi Acharya

Research output: Contribution to journalReview articlepeer-review

31 Citations (SciVal)

Abstract

Botulinum neurotoxins (BoNTs) cause flaccid paralysis by inhibiting neurotransmission at cholinergic nerve terminals. Each BoNT consists of three domains that are essential for toxicity: the binding domain, the translocation domain, and the catalytic light-chain domain. BoNT modular architecture is associated with a multistep mechanism that culminates in the intracellular proteolysis of SNARE (soluble N-ethylmaleimide-sensitive-fusion-protein attachment protein receptor) proteins, which prevents synaptic vesicle exocytosis. As the most toxic proteins known, BoNTs have been extensively studied and are used as pharmaceutical agents to treat an increasing variety of disorders. This review summarizes the level of sophistication reached in BoNT engineering and highlights the diversity of approaches taken to utilize the modularity of the toxin. Improved efficiency and applicability have been achieved by direct mutagenesis and interserotype domain rearrangement. The scope of BoNT activity has been extended to nonneuronal cells and offers the basis for novel biomolecules in the treatment of secretion disorders.

Original languageEnglish
Pages (from-to)27-51
Number of pages25
JournalAnnual Review of Pharmacology and Toxicology
Volume54
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Biopharmaceuticals
  • Hypersecretory disorders
  • Intracellular transporter
  • Protein engineering

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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