The transthyretin amyloidoses: From delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug

Steven M. Johnson, Stephen Connelly, Colleen Fearns, Evan T. Powers, Jeffery W. Kelly

Research output: Contribution to journalReview article

198 Scopus citations

Abstract

Transthyretin (TTR) is one of the many proteins that are known to misfold and aggregate (i.e., undergo amyloidogenesis) in vivo. The process of TTR amyloidogenesis causes nervous system and/or heart pathology. While several of these maladies are associated with mutations that destabilize the native TTR quaternary and/or tertiary structure, wild-type TTR amyloidogenesis also leads to the degeneration of postmitotic tissue. Over the past 20 years, much has been learned about the factors that influence the propensity of TTR to aggregate. This biophysical information led to the development of a therapeutic strategy, termed kinetic stabilization, to prevent TTR amyloidogenesis. This strategy afforded the drug tafamidis which was recently approved by the European Medicines Agency for the treatment of TTR familial amyloid polyneuropathy, the most common familial TTR amyloid disease. Tafamidis is the first and currently the only medication approved to treat TTR familial amyloid polyneuropathy. Here we review the biophysical basis for the kinetic stabilization strategy and the structure-based drug design effort that led to this first-in-class pharmacologic agent.

Original languageEnglish (US)
Pages (from-to)185-203
Number of pages19
JournalJournal of molecular biology
Volume421
Issue number2-3
DOIs
StatePublished - Aug 10 2012
Externally publishedYes

Keywords

  • amyloid
  • kinetic stabilization
  • polyneuropathy
  • transthyretin

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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