Inhibiting transthyretin conformational changes that lead to amyloid fibril formation

Inhibiting transthyretin conformational changes that lead to amyloid fibril formation

^*Department of Chemistry and Skaggs Institute of Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road MB 12, La Jolla, CA 92037; and ^‡Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843

Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved September 1, 1998 (received for review May 20, 1998)

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.

Footnotes

↵ † S.A.P. and T.K. contributed equally to this work.
↵ § To whom reprint requests should be addressed. e-mail: jkelly{at}scripps.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, Biology Department, Brookhaven National Laboratory, Upton, NY 11973 [PDB ID codes 1BMZ (apo⋅TTR) and 1BM7 (TTR⋅Flu)].
ABBREVIATIONS:

FAP,

familial amyloid polyneuropathy;

TTR,

transthyretin;

SSA,

senile systemic amyloidosis;

Flu,

flufenamic acid;

T4,

thyroxine