Inhibiting transthyretin conformational changes that lead to amyloid fibril formation.
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.
Peterson
S A
SA
Department of Chemistry and Skaggs Institute of Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road MB 12, La Jolla, CA 92037, USA.
Klabunde
T
T
Lashuel
H A
HA
Purkey
H
H
Sacchettini
J C
JC
Kelly
J W
JW
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D000686:Amyloidosis; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli; D005439:Flufenamic Acid / Q000494:pharmacology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011228:Prealbumin / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D000682:Amyloid; D046911:Macromolecular Substances; D011228:Prealbumin; D011994:Recombinant Proteins; D005439:Flufenamic Acid