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Cell based screening of inhibitors of transthyretin aggregation.
Reixach, Natàlia; Adamski-Werner, Sara L; Kelly, Jeffery W; Koziol, James; Buxbaum, Joel N.
Afiliação
  • Reixach N; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Biochem Biophys Res Commun ; 348(3): 889-97, 2006 Sep 29.
Article em En | MEDLINE | ID: mdl-16904635
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.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pré-Albumina / Anti-Inflamatórios não Esteroides Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Humans Idioma: En Revista: Biochem Biophys Res Commun Ano de publicação: 2006 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pré-Albumina / Anti-Inflamatórios não Esteroides Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Humans Idioma: En Revista: Biochem Biophys Res Commun Ano de publicação: 2006 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos