title: Botulinum neurotoxin: Progress in negating its neurotoxicity; and in extending its therapeutic utility via molecular engineering. MiniReview.
abstract: While the poisonous effects of botulinum neurotoxin (BoNT) have been recognized since antiquity, the overall actions and mechanisms of effects of BoNT have been elucidated primarily over the past several decades. The general utility of BoNT is described in the paper, but the focus is mainly on the approaches towards negating the toxic effects of BoNT, and on the projection of an engineered BoNT molecule serving as a Trojan Horse to deliver a therapeutic load for treatment of a host of medical disorders. The BoNT molecule is configured with a binding domain, a zinc-dependent protease with specificity primarily for vesicular proteins, and a translocation domain for delivery of the metalloprotease into the cytoplasm. The anti-toxin approaches for BoNT include the use of vaccines, antibodies, block of BoNT binding or translocation, inhibition of metalloprotease activity, impeded translocation of the protease/catalytic domain, and inhibition of the downstream Src signaling pathway. Projections of BoNT as a therapeutic include its targeting to non-cholinergic nerves, also targeting to non-neuronal cells for treatment of hypersecretory disorders (e.g., cystic fibrosis), and treatment of hormonal disorders (e.g., acromegaly). Still in the exploratory phase, there is the expectation of major advances in BoNT neuroprotective strategies and burgeoning utility of engineered BoNTs as therapeutics.
authors.affiliation: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, P.O. Box 70577, Johnson City, TN 37614, USA. Electronic address: kostrzew@etsu.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kostrzewa
authors.affiliation: Walgreen's Pharmacy, Colonial Heights, TN 37663, USA.
authors.forename: Rose Anna
authors.initials: RA
authors.lastname: Kostrzewa
authors.affiliation: North Alabama ENT Associates, Huntsville, AL 35801, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Kostrzewa
mesh_terms: D000172:Acromegaly / Q000188:drug therapy*; D001905:Botulinum Toxins / Q000235:genetics / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D015202:Protein Engineering
chemical_list: D001905:Botulinum Toxins
keywords: Botulinum; Neurotoxin; Therapeutic; Trojan horse