Expanding use of botulinum toxin

Bhidayasiri, Roongroj; Truong, Daniel D.

doi:10.1016/j.jns.2005.04.017

Cited by 92 publications

(69 citation statements)

References 99 publications

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“…Medically , BTX is used for the treatment of many diseases including blepharospasm, spasmodic torticollis, extremity dystonia and hemifacial spasm. In addition, it is used for the treatment of palmar and axillary hyperhidrosis caused by autonomous nervous system hyperactivity (33)(34)(35)(36). Physiologically, BTX irreversibly binds to presynaptic neurons at the neuromuscular junction and inhibits the release of acetylcholine that causes muscle relaxation (37).…”

Section: Resultsmentioning

confidence: 99%

Prevention of unfavourable effects of cigarette smoke on flap viability using botulinum toxin in random pattern flaps: An experimental study

Karayel¹,

Kaya²,

Çaydere³

et al. 2015

CAN J PLAST SURG

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Section: Resultsmentioning

confidence: 99%

Prevention of unfavourable effects of cigarette smoke on flap viability using botulinum toxin in random pattern flaps: An experimental study

Karayel¹,

Kaya²,

Çaydere³

et al. 2015

CAN J PLAST SURG

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“…In addition, BoNT is the most widely utilized protein for human therapy (37) for numerous neurological disorders from migraines to muscle trauma to physical disabilities (38). BoNT serotype A is used in these therapies, based upon the ability to produce relatively pure amounts of the holotoxin and the longevity of LC action in neurons (39,40). Thus, understanding the substrate specificity of LC/A should also provide insight into the modification of BoNT to optimize therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Substrate Recognition by Botulinum Neurotoxin Serotype A

Chen

Kim

Barbieri

2007

Journal of Biological Chemistry

105

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Botulinum neurotoxins (BoNTs) are zinc proteases that cleave SNARE proteins to elicit flaccid paralysis by inhibiting neurotransmitter-carrying vesicle fusion to the plasma membrane of peripheral neurons. Unlike other zinc proteases, BoNTs recognize extended regions of SNAP25 for cleavage; however, the molecular basis for this extended substrate recognition is unclear. Here, we define a multistep mechanism for recognition and cleavage of SNAP25 by BoNT/A. SNAP25 initially binds along the belt region of BoNT/A, which aligns the P5 residue to the S5 pocket at the periphery of the active site. Although the exact order of each step of recognition of SNAP25 by BoNT/A at the active site is not clear, the initial binding could subsequently orient the P4-residue of SNAP25 to form a salt bridge with the S4-residue, which opens the active site allowing the P1-residue access to the S1-pocket. Subsequent hydrophobic interactions between the P3 residue of SNAP25 and the S3 pocket optimize alignment of the scissile bond for cleavage. This explains how the BoNTs recognize and cleave specific coiled SNARE substrates and provides insight into the development of inhibitors to prevent botulism. Botulinum neurotoxins (BoNTs)2 are the most potent protein toxins for humans (1). There are seven BoNT serotypes, A-G, with serotypes A, B, and E responsible for most natural human intoxications (2). BoNT serotypes are defined by the specificity of antibody neutralization where antibodies that neutralize one serotype fail to neutralize other serotypes. There are two licensed vaccines against botulism, a pentavalent vaccine against serotypes A-E (3) and a heptavalent vaccine against serotypes A-G (4). However, these vaccines are produced from chemically inactivated BoNT produced in Clostridium botulinum and are currently in limited supply. BoNT intoxication has significant morbidity and mortality (5, 6). Thus, there is a need to develop more efficient vaccines and therapies against botulism.BoNTs are zinc proteases that elicit flaccid paralysis by inhibiting the fusion of neurotransmitter-carrying vesicles to the plasma membrane of peripheral neurons. BoNTs are 150-kDa single chain proteins that are activated by proteolysis to generate disulfidelinked di-chain proteins. BoNTs are organized into three functional domains, an N-terminal catalytic domain (light chain, LC), an internal translocation domain (HCT), and a C-terminal receptor binding domain (HCR) (7,8). The tropism for neurons is due to the affinity of BoNT for receptors on peripheral neurons (7). BoNTs enter neurons via receptor-mediated endocytosis, and upon acidification of the early endosome LC is translocated into the cytosol. LCs cleave neurotransmitter vesicle fusion proteins; BoNT/A cleaves SNAP25 between residues 197 and 198, and BoNT/E cleaves SNAP25 between residues 180 and 181 (9). BoNT/C cleaves both SNAP25 and syntaxin (10), whereas the other BoNT serotypes and tetanus toxin cleave the vesicle-associated membrane protein (11).Unlike other zinc proteases, BoNTs recognize...

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“…BoNTs are easily produced and may be delivered via food "spiking" and/or aerosol route. [2][3][4][5][6] Furthermore, as BoNTs are now used to treat a range of medical conditions, and in many cosmetic applications, 3,[7][8][9][10][11][12][13][14] they are being produced in increasing quantities, making their misuse, accidental overdosing, and/or instances of adverse side effects 15 more likely. Neither the currently available CDC BoNT equine antitoxins, which can cause adverse anaphylaxis and serum sickness, 16 nor experimental antibodies can counter these enzymes once they are inside neurons.…”

Section: Introductionmentioning

confidence: 99%

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

et al. 2007

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We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dualfunction BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC 50 's ranged from 3.2 to 17 µM). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.

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Expanding use of botulinum toxin

Cited by 92 publications

References 99 publications

Prevention of unfavourable effects of cigarette smoke on flap viability using botulinum toxin in random pattern flaps: An experimental study

Prevention of unfavourable effects of cigarette smoke on flap viability using botulinum toxin in random pattern flaps: An experimental study

Mechanism of Substrate Recognition by Botulinum Neurotoxin Serotype A

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

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