Correction: The Use of Small Molecules to Investigate Molecular Mechanisms and Therapeutic Targets for Treatment of Botulinum Neurotoxin A Intoxication

ZusammenfassungDie Behandlung neuropathischer Schmerzen mit systemisch wirksamen oral verabreichten Pharmaka ist bei vielen Patienten wirksam, kann jedoch zu zentralnervösen unerwünschten Wirkungen wie Müdigkeit oder Schwindel führen. Daher sind in den letzten Jahren topische Therapien in das Zentrum der Aufmerksamkeit gerückt. Botulinumtoxin, etabliert in der Therapie von Dystonien und Spastik, wurde zunehmend bei Schmerzerkrankungen getestet, hierbei ist Botulinum-Neurotoxin A der am besten untersuchte Serotyp. Die häufigsten Indikationen waren Schmerzen im Trigeminusversorgungsbereich und periphere neuropathische Schmerzen. Bei den meisten Studien war Botulinum-Neurotoxin A Placebo deutlich überlegen. Präklinische Studien zum Wirkmechanismus erbrachten die Erkenntnis, dass neben dem erwarteten peripheren Effekt sehr wahrscheinlich auch eine zentrale Reduktion der Ausschüttung von exzitatorischen Neurotransmittern an der Wirkung beteiligt ist.

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Komplexproteinfreies Botulinum Neurotoxin A - Blepharospasmus und Torticollis

psychoneuro ◽

10.1055/s-2007-991580 ◽

2007 ◽

Vol 33 (9) ◽

pp. 376-376

Keyword(s):

Botulinum Neurotoxin ◽

Botulinum Neurotoxin A

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Primary Cultures of Embryonic Chicken Neurons for Sensitive Cell-Based Assay of Botulinum Neurotoxin: Implications for Therapeutic Discovery

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057106299163 ◽

2007 ◽

Vol 12 (3) ◽

pp. 370-377 ◽

Cited By ~ 29

Author(s):

Andrea M. Stahl ◽

Gordon Ruthel ◽

Edna Torres-Melendez ◽

Tara A. Kenny ◽

Rekha G. Panchal ◽

...

Keyword(s):

Nervous System ◽

Botulinum Toxin ◽

Neutralizing Antibodies ◽

Botulinum Neurotoxin ◽

Potent Inhibitor ◽

Primary Cultures ◽

Embryonic Chick ◽

Sensitive Cell ◽

Botulinum Neurotoxin A ◽

Therapeutic Compounds

Botulinum toxin is an exceedingly potent inhibitor of neurotransmission across the neuromuscular junction, causing flaccid paralysis and death. The potential for misuse of this deadly poison as a bioweapon has added a greater urgency to the search for effective therapeutics. The development of sensitive and efficient cell-based assays for the evaluation of toxin antagonists is crucial to the rapid and successful identification of therapeutic compounds. The authors evaluated the sensitivity of primary cultures from 4 distinct regions of the embryonic chick nervous system to botulinum neurotoxin A (BoNT/A) cleavage of synaptosomal-associated protein of 25 kD (SNAP-25). Although differences in sensitivity were apparent, SNAP-25 cleavage was detectable in neuronal cells from each of the 4 regions within 3 h at BoNT/A concentrations of 1 nM or lower. Co-incubation of chick neurons with BoNT/A and toxin-neutralizing antibodies inhibited SNAP-25 cleavage, demonstrating the utility of these cultures for the assay of BoNT/A antagonists. ( Journal of Biomolecular Screening 2007:370-377)

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Intratracheal inoculation of AHc vaccine induces protection against aerosolized botulinum neurotoxin A challenge in mice

npj Vaccines ◽

10.1038/s41541-021-00349-w ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Changjiao Gan ◽

Wenbo Luo ◽

Yunzhou Yu ◽

Zhouguang Jiao ◽

Sha Li ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Clostridium Botulinum ◽

Freeze Drying ◽

Botulinum Neurotoxin ◽

Secretory Iga ◽

Immune Protection ◽

Dry Powder ◽

Botulinum Neurotoxin A ◽

Spray Freeze Drying

AbstractBotulinum neurotoxin (BoNT), produced by Clostridium botulinum, is generally known to be the most poisonous of all biological toxins. In this study, we evaluate the protection conferred by intratracheal (i.t.) inoculation immunization with recombinant Hc subunit (AHc) vaccines against aerosolized BoNT/A intoxication. Three AHc vaccine formulations, i.e., conventional liquid, dry powder produced by spray freeze drying, and AHc dry powder reconstituted in water are prepared, and mice are immunized via i.t. inoculation or subcutaneous (s.c.) injection. Compared with s.c.-AHc-immunized mice, i.t.-AHc-immunized mice exhibit a slightly stronger protection against a challenge with 30,000× LD50 aerosolized BoNT/A. Of note, only i.t.-AHc induces a significantly higher level of toxin-neutralizing mucosal secretory IgA (SIgA) production in the bronchoalveolar lavage of mice. In conclusion, our study demonstrates that the immune protection conferred by the three formulations of AHc is comparable, while i.t. immunization of AHc is superior to s.c. immunization against aerosolized BoNT/A intoxication.

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Strategies to Counteract Botulinum Neurotoxin A: Nature’s Deadliest Biomolecule

Accounts of Chemical Research ◽

10.1021/acs.accounts.9b00261 ◽

2019 ◽

Vol 52 (8) ◽

pp. 2322-2331 ◽

Cited By ~ 3

Author(s):

Lucy Lin ◽

Margaret E. Olson ◽

Lisa M. Eubanks ◽

Kim D. Janda

Keyword(s):

Botulinum Neurotoxin ◽

Botulinum Neurotoxin A

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Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

Nature Communications ◽

10.1038/s41467-020-20782-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Francesco Simone Ruggeri ◽

Johnny Habchi ◽

Sean Chia ◽

Robert I. Horne ◽

Michele Vendruscolo ◽

...

Keyword(s):

Small Molecules ◽

Single Molecule ◽

Protein Misfolding ◽

Molecular Mechanisms ◽

Chemical Sensitivity ◽

Incomplete Knowledge ◽

Parkinson’S Diseases ◽

Aggregation Inhibitor ◽

Misfolding Diseases

AbstractSignificant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.

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