Inhibiting transthyretin amyloid fibril formation via protein stabilization.
Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases. Herein, we demonstrate conclusively that thyroxine (10.8 microM) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation. In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism. Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine. These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases. This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis--i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.
Miroy
G J
GJ
Department of Chemistry, Texas A&M University, College Station 77843-3255, USA.
Lai
Z
Z
Lashuel
H A
HA
Peterson
S A
SA
Strang
C
C
Kelly
J W
JW
D000686:Amyloidosis; D001665:Binding Sites; D003001:Cloning, Molecular; D004926:Escherichia coli; D006801:Humans; D007700:Kinetics; D008961:Models, Structural; D010636:Phenols / Q000494:pharmacology*; D011228:Prealbumin / Q000737:chemistry* / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects*; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects; D013974:Thyroxine / Q000494:pharmacology*
D010636:Phenols; D011228:Prealbumin; D011994:Recombinant Proteins; C066859:2,4,6-triiodophenol; D013974:Thyroxine