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Cell based screening of inhibitors of transthyretin aggregation

Academic Article
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Overview

authors

  • Reixach, Natalia
  • Adamski-Werner, S. L.
  • Kelly, Jeffery
  • Koziol, James
  • Buxbaum, Joel

publication date

  • September 2006

journal

  • Biochemical and Biophysical Research Communications  Journal

abstract

  • The amyloidoses are the extracellular subset of a group of diseases in which in vivo protein misfolding leads to a pathologic gain of function, i.e., aggregation leading to protein deposition, with subsequent tissue damage. Wild-type and mutant transthyretins (TTR) are the etiologic agents in prototypic systemic amyloidoses. We describe a cell-based assay that measures the cytotoxicity of physiologic concentrations of the amyloidogenic Val30Met TTR variant (V30M TTR) using cells of the same lineage as the in vivo tissue target of amyloid deposition. We have utilized the assay to screen small molecules for their capacity to inhibit the TTR-induced cell damage. We compared the inhibitory activity of each compound with its ability to prevent TTR fibril formation in vitro. Our results emphasize the importance of screening compounds under physiologic conditions. Moreover, if a common conformational intermediate is responsible for cell death in all the amyloid diseases, the cell-based assay has the potential to aid in the discovery of compounds useful in the treatment of amyloidoses caused by other misfolded proteins as well as those caused by TTR.

subject areas

  • Amyloidosis
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Survival
  • Diflunisal
  • Drug Evaluation, Preclinical
  • Humans
  • Methionine
  • Microfibrils
  • Neurons
  • Prealbumin
  • Stilbenes
  • Valine
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Research

keywords

  • amyloidosis
  • cytotoxicity inhibition
  • non-steroidal anti-inflammatory drugs
  • resveratrol
  • transthyretim
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Identity

International Standard Serial Number (ISSN)

  • 0006-291X

Digital Object Identifier (DOI)

  • 10.1016/j.bbrc.2006.07.109

PubMed ID

  • 16904635
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Additional Document Info

start page

  • 889

end page

  • 897

volume

  • 348

issue

  • 3

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