Inhibiting transthyretin conformational changes that lead to amyloid fibril formation

Scott A. Peterson, Thomas Klabunde, Hilal A. Lashuel, Hans Purkey, James C. Sacchettini, Jeffrey W. Kelly

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

Insoluble protein fibrils resulting from the self-assembly of a conformational intermediate are implicated as the causative agent in several severe human amyloid diseases, including Alzheimer's disease, familial amyloid polyneuropathy, and senile systemic amyloidosis. The latter two diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of the lysosome. Here we demonstrate that flufenamic acid (Flu) inhibits the conformational changes of TTR associated with amyloid fibril formation. The crystal structure of TTR complexed with flu demonstrates that Flu mediates intersubunit hydrophobic interactions and intersubunit hydrogen bonds that stabilize the normal tetrameric fold of TTR. A small-molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a possible approach to treat amyloid diseases. Molecules such as Flu also provide the means to rigorously test the amyloid hypothesis, i.e., the apparent causative role of amyloid fibrils in amyloid disease.

Original languageEnglish
Pages (from-to)12956-12960
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number22
DOIs
Publication statusPublished - 27 Oct 1998
Externally publishedYes

Fingerprint

Prealbumin
Amyloid
Flufenamic Acid
Familial Amyloid Neuropathies
Protein Conformation
Amyloidosis
Lysosomes
Hydrophobic and Hydrophilic Interactions
Hydrogen
Alzheimer Disease

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. / Peterson, Scott A.; Klabunde, Thomas; Lashuel, Hilal A.; Purkey, Hans; Sacchettini, James C.; Kelly, Jeffrey W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 22, 27.10.1998, p. 12956-12960.

Research output: Contribution to journalArticle

Peterson, Scott A. ; Klabunde, Thomas ; Lashuel, Hilal A. ; Purkey, Hans ; Sacchettini, James C. ; Kelly, Jeffrey W. / Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. In: Proceedings of the National Academy of Sciences of the United States of America. 1998 ; Vol. 95, No. 22. pp. 12956-12960.
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