Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: A focus on the transthyretin amyloidoses

Steven M. Johnson, R. Luke Wiseman, Yoshiki Sekijima, Nora S. Green, Sara L. Adamski-Werner, Jeffery W. Kelly

Research output: Contribution to journalReview article

215 Scopus citations

Abstract

Small molecule-mediated protein stabilization inside or outside of the cell is a promising strategy to treat protein misfolding/ misassembly diseases. Herein we focus on the transthyretin (TTR) amyloidoses and demonstrate that preferential ligand binding to and stabilization of the native state over the dissociative transition state raises the kinetic barrier of dissociation (rate-limiting for amyloidogenesis), slowing and in many cases preventing TTR amyloid fibril formation. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits also imparts kinetic stability on the tetramer and ameliorates amyloidosis in humans, it is likely that small molecule-mediated native state kinetic stabilization will also alleviate TTR amyloidoses.

Original languageEnglish (US)
Pages (from-to)911-921
Number of pages11
JournalAccounts of Chemical Research
Volume38
Issue number12
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)

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