Botulinum neurotoxin: Progress in negating its neurotoxicity; and in extending its therapeutic utility via molecular engineering. MiniReview

Kostrzewa, Richard M.; Kostrzewa, Rose Anna; Kostrzewa, John P.

doi:10.1016/j.peptides.2015.07.003

Cited by 6 publications

(8 citation statements)

References 111 publications

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“…Treatment of BoNT intoxication following a bioterrorist attack, natural outbreak or clinical overdose requires a therapeutic agent that is unconstrained by a limited therapeutic window (Kostrzewa et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

Toxicon

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Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.

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Section: Introductionmentioning

confidence: 99%

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

Toxicon

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“…Despite its inherent lethality, there are relatively few cases of Botulism disease each year, with virtually all reports involving improper food preparation resulting in C. botulinum contamination. 633 The earliest documented cases of Botulism date to the 1800s, 634 with examples of bioterrorism involving Botulism including the Japanese invasion of Manchuria in the 1930s, the Iraqi production and stockpiling of BoNT, and the failed Aum Shinrikyo attacks in Japan from 1990 to 1995. 632 BoNT acts by disrupting acetylcholine neurotransmission resulting in muscle flaccidity and paralysis.…”

Section: Chemical Reviewsmentioning

confidence: 99%

“…Additionally, the SAR around inhibitor development has been rather flat in that most small-molecule inhibitors have activity >1 μM, indicating that there is room for inhibitor improvement. It is worth noting that there is limited availability equine-derived antibodies to treat BoNT exposure; however, these must be administered with a narrow therapeutic window of approximately 24 h post exposure before the toxin is taken up within the nerve synapse. ,,, In the event of an unexpected bioterrorism attack involving BoNT, prophylactic antibiotic treatment is not realistic, and would have catastrophic impact on civilian areas. Therefore, it is of great importance to improve assay screening protocls for BoNT to develop new inhibitors aginst this enzyme.…”

Section: Peptidases (Ec 34)mentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

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“…The vesicular acidic pH triggers a conformational switch of BoNT, which favors the HN-mediated translocation of the light chain of BoNT across the endosomal membrane into the cytoplasm [ 15 ]. The reducing cytosolic environment enhances disulfide bond cleavage, allowing the catalytic LC zinc protease domain of BoNT to freely act, cleaving the substrate represented by different polypeptide portions of the SNARE complex depending on the BoNT serotype [ 8 , 16 ]. In particular, LC zinc proteases of BoNT-A and BoNT-E breakdown SNAP25, proteases of BoNT-B, BoNT-D, BoNT-F and BoNT-G hydrolyze VAMP/synaptobrevin (vesicle-associated membrane protein) and BoNT-C degrades either SNAP25 (synaptosomal associated membrane protein of 25 kDa) or syntaxin [ 14 ] ( Figure 2 ).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Therapeutic Applications of Botulinum Neurotoxins in Veterinary Medicine

Turin,

Piccione,

Crosa

et al. 2023

Veterinary Sciences

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Botulinum neurotoxins (BoNTs) are emerging as multipurpose therapeutic compounds for the treatment of several different syndromes involving peripheral and central nervous systems, and muscular and musculoskeletal disorders both in human and veterinary medicine. Therefore, the study of BoNTs is rapidly developing and identifying newly produced BoNT variants. Efforts should be made to clarify the biological and pharmacological characteristics of these novel BoNTs as well as the natural ones. The high potential of BoNTs as a therapeutic compound for medical syndromes lies in its ability to reach a specific cell type while bypassing other cells, thus having mild or no side effects. In this paper the recent developments in BoNTs are reviewed with the aim of analyzing the current knowledge on BoNTs’ biological mechanisms of action, immunogenicity, formulations, and therapeutic applications in the veterinary field, highlighting advantages and drawbacks and identifying the gaps to be filled in order to address research priorities.

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Botulinum neurotoxin: Progress in negating its neurotoxicity; and in extending its therapeutic utility via molecular engineering. MiniReview

Cited by 6 publications

References 111 publications

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Targeting Metalloenzymes for Therapeutic Intervention

Therapeutic Applications of Botulinum Neurotoxins in Veterinary Medicine

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