Recombinant Derivatives of Clostridial Neurotoxins as Delivery Vehicles for Proteins and Small Organic Molecules

Zdanovskaia, Marina V.; Los, Georgyi V.; Zdanovsky, Alexey G.

doi:10.1023/a:1007164619921

Cited by 10 publications

(2 citation statements)

References 28 publications

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“…The natural biology and ability of the BoNT heavy chain to be endocytosed and translocated may represent an opportunity to use it as a delivery vehicle for inhibitors. Heavy chain (HC) of the BoNT has been shown to be an effective delivery vehicle to deliver molecules into the BoNT specific nerve cells [115,116]. BoNT HC itself is not toxic, and therefore, provides a safe delivery vehicle.…”

Section: Delivery Systemmentioning

confidence: 99%

Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus

Yeung¹,

Meanwell²

2007

IDDT

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This article summarizes the significant developments and new discoveries in both the virology and antiviral research associated with the severe acute respiratory syndrome coronavirus (SARS CoV) that were reported in 2005 and 2006. Areas reviewed include genomic studies and the identification of bat-SARS CoV, spike protein and host cell entry, nucleocapsid protein, accessory proteins, non-structural proteins of the replicase complex, viral proteases and their inhibitors, and clinical treatment of SARS with ribavirin.

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Section: Delivery Systemmentioning

confidence: 99%

Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus

Yeung¹,

Meanwell²

2007

IDDT

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“…One current therapeutic design approach is to identify compounds that inhibit intracellular LC activity, as these can be administered postexposure to aid in long-term treatment. While peptides − and aptamers have been described that inhibit LC/A activity, no compound has advanced clinically. These compounds are challenging to develop as therapeutics given that they do not readily enter cells.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screening Uncovers Novel Botulinum Neurotoxin Inhibitor Chemotypes

et al. 2016

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Botulism is caused by potent and specific bacterial neurotoxins that infect host neurons and block neurotransmitter release. Treatment for botulism is limited to administration of an antitoxin within a short time window, before the toxin enters neurons. Alternatively, current botulism drug development targets the toxin light chain, which is a zinc-dependent metalloprotease that is delivered into neurons and mediates long-term pathology. Several groups have identified inhibitory small molecules, peptides, or aptamers, although no molecule has advanced to the clinic due to a lack of efficacy in advanced models. Here we used a homogeneous high-throughput enzyme assay to screen three libraries of drug-like small molecules for new chemotypes that modulate recombinant botulinum neurotoxin light chain activity. High-throughput screening of 97088 compounds identified numerous small molecules that activate or inhibit metalloprotease activity. We describe four major classes of inhibitory compounds identified, detail their structure-activity relationships, and assess their relative inhibitory potency. A previously unreported chemotype in any context of enzyme inhibition is described with potent submicromolar inhibition (Ki = 200-300 nM). Additional detailed kinetic analyses and cellular cytotoxicity assays indicate the best compound from this series is a competitive inhibitor with cytotoxicity values around 4-5 μM. Given the potency and drug-like character of these lead compounds, further studies, including cellular activity assays and DMPK analysis, are justified.

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Clostridial neurotoxins: structure-function led design of new therapeutics

Chaddock¹,

Marks²

2006

Cell. Mol. Life Sci.

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The neurotoxins produced by various species of Clostridia are the causative agents of botulism and tetanus. The ability of the toxins, specifically those of the botulinum neurotoxin family, to disrupt neurotransmission has been exploited for use in several medical indications and now represents the therapeutic option of choice in a number of cases. Clostridial neurotoxins have been discovered to have a multi-domain structure that is shared between the various proteins of the family, and it has also been determined that each domain contributes a specific role to the holotoxin. The extensive use of recombinant expression approaches, along with solution of multiple crystallographic structures of individual domains, has enabled researchers to explore structurefunction relationships of the toxin domains more closely. These advances have facilitated a greater understanding of the potential use of individual domains for a wide variety of purposes, including the development of new therapeutics.

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Recombinant Derivatives of Clostridial Neurotoxins as Delivery Vehicles for Proteins and Small Organic Molecules

Cited by 10 publications

References 28 publications

Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus

Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus

High-Throughput Screening Uncovers Novel Botulinum Neurotoxin Inhibitor Chemotypes

Clostridial neurotoxins: structure-function led design of new therapeutics

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