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Pivot Concepts:
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Target Concepts:
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Query: EC:3.4.24.69 (
botulinum neurotoxin
)
1,901
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Botulinum neurotoxin is a potent inhibitor of acetylcholine secretion and acts by cleaving members of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor family, which are critical to exocytotic vesicular secretion. However, the potential of
botulinum neurotoxin
for treating secretory disease is limited both by its neural selectivity and the necessity for direct injection into the relevant target tissue. To circumvent these limitations, a technology platform called targeted secretion inhibitors (TSIs) is being developed. TSIs are derived from
botulinum neurotoxin
but are retargeted to specific cell types to inhibit aberrant secretion. A TSI called qGHRH-LHN/D, with a GHRH receptor targeting domain and designed to specifically inhibit pituitary somatotroph GH release through cleavage of the N-ethylmaleimide-sensitive factor-attachment protein receptor protein, vesicle-associated membrane protein (VAMP), has recently been described. Here we show this TSI activates GHRH receptors in primary cultured rat pituicytes is internalized into these cells, depletes VAMP-3, and inhibits phorbol-12-myristate-13-acetate-induced GH secretion. In vivo studies show that this TSI, but not one with an inactive catalytic unit, produces a dose-dependent inhibition of pulsatile GH secretion, thus confirming its mechanism of action through VAMP cleavage. Selectivity of action has been shown by the lack of effect of this TSI in vivo on secretion from thyrotrophs, corticotrophs, and gonadotrophs. In the absence of suitable in vivo models, these data provide proof of concept for the use of somatotroph-targeted TSIs in the treatment of
acromegaly
and moreover raise the potential that TSIs could be used to target other diseases characterized by hypersecretion.
...
PMID:GHRH receptor-targeted botulinum neurotoxin selectively inhibits pulsatile GH secretion in male rats. 2382 27
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.
...
PMID:Botulinum neurotoxin: Progress in negating its neurotoxicity; and in extending its therapeutic utility via molecular engineering. MiniReview. 2619 75
