title: Engineered botulinum neurotoxins as new therapeutics.
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.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom; email: bsskra@bath.ac.uk.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Masuyer
authors.forename: John A
authors.initials: JA
authors.lastname: Chaddock
authors.forename: Keith A
authors.initials: KA
authors.lastname: Foster
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D002460:Cell Line; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D009498:Neurotoxins; D011487:Protein Conformation; D015202:Protein Engineering; D059748:Proteolysis / Q000187:drug effects; D050600:SNARE Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D009498:Neurotoxins; D050600:SNARE Proteins; D001905:Botulinum Toxins