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

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.

• Authors: Steven M Johnson, Stephen Connelly, Colleen Fearns, Evan T Powers, Jeffery W Kelly
• Journal: Journal of molecular biology (J Mol Biol) Vol. 421 Issue 2-3 Pg. 185-203 (Aug 10 2012) ISSN: 1089-8638 [Electronic] Netherlands
• PMID: 22244854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Prealbumin

Topics

• Amyloidosis (metabolism)
• Animals
• Drug Approval
• Humans
• Kinetics
• Models, Molecular
• Prealbumin (chemistry, metabolism)
• Protein Conformation