Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses

Stephen Connelly, Sungwook Choi, Steven M. Johnson, Jeffery W. Kelly, Ian A. Wilson

Research output: Contribution to journalReview article

130 Scopus citations

Abstract

Small molecules that bind to normally unoccupied thyroxine (T4) binding sites within transthyretin (TTR) in the blood stabilize the tetrameric ground state of TTR relative to the dissociative transition state and dramatically slow tetramer dissociation, the rate-limiting step for the process of amyloid fibril formation linked to neurodegeneration and cell death. These so-called TTR kinetic stabilizers have been designed using structure-based principles and one of these has recently been shown to halt the progression of a human TTR amyloid disease in a clinical trial, providing the first pharmacologic evidence that the process of amyloid fibril formation is causative. Structure-based design has now progressed to the point where highly selective, high affinity TTR kinetic stabilizers that lack undesirable off-target activities can be produced with high frequency.

Original languageEnglish (US)
Pages (from-to)54-62
Number of pages9
JournalCurrent Opinion in Structural Biology
Volume20
Issue number1
DOIs
StatePublished - Feb 1 2010

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ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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