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Targeting botulinum A cellular toxicity: a prodrug approach

Academic Article
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Overview

authors

  • Silhar, P.
  • Eubanks, L. M.
  • Seki, H.
  • Pellet, S.
  • Javor, S.
  • Tepp, W. H.
  • Johnson, E. A.
  • Janda, Kim

publication date

  • 2013

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • The botulinum neurotoxin light chain (LC) protease has become an important therapeutic target for postexposure treatment of botulism. Hydroxamic acid based small molecules have proven to be potent inhibitors of LC/A with nanomolar Ki values, yet they lack cellular activity conceivably due to low membrane permeability. To overcome this potential liability, we investigated two prodrug strategies, 1,4,2-dioxazole and carbamate, based on our 1-adamantylacetohydroxamic acid scaffold. The 1,4,2-dioxazole prodrug did not demonstrate cellular activity, however, carbamates exhibited cellular potency with the most active compound displaying an EC50 value of 20 μM. Cellular trafficking studies were conducted using a "fluorescently silent" prodrug that remained in this state until cellular uptake was complete, which allowed for visualization of the drug's release inside neuronal cells. In sum, this research sets the stage for future studies leveraging the specific targeting and delivery of these prodrugs, as well as other antibotulinum agents, into neuronal cells.

subject areas

  • Anti-Bacterial Agents
  • Azoles
  • Botulinum Toxins, Type A
  • Carbamates
  • Cell Survival
  • Cells, Cultured
  • Clostridium botulinum
  • Drug Stability
  • Half-Life
  • Humans
  • Hydroxamic Acids
  • Microscopy, Confocal
  • Models, Chemical
  • Molecular Structure
  • Neurons
  • Prodrugs
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Identity

PubMed Central ID

  • PMC3880648

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm400873n

PubMed ID

  • 24127873
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Additional Document Info

start page

  • 7870

end page

  • 7879

volume

  • 56

issue

  • 20

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