Engineered botulinum neurotoxins as new therapeutics

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...

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Bibliographic Details
Published in:Annual review of pharmacology and toxicology 2014-01, Vol.54 (1), p.27-51
Main Authors: Masuyer, Geoffrey, Chaddock, John A, Foster, Keith A, Acharya, K Ravi
Format: Article
Language:English
Subjects:
Animals
Botulinum Toxins - chemistry
Botulinum Toxins - genetics
Botulinum Toxins - pharmacology
Cell Line
Exocytosis - drug effects
Humans
Neurotoxins
Protein Conformation
Protein Engineering
Proteolysis - drug effects
SNARE Proteins - metabolism
Synaptic Transmission - drug effects
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Summary: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.
ISSN:0362-1642
1545-4304
DOI:10.1146/annurev-pharmtox-011613-135935