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 demon strate conclusively that thyroxine (10.8 mu M) inhibits TTR fibril for mation efficiently in vitro and does so by stabilizing the tetramer ag ainst 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 als o inhibits TTR fibril formation by this mechanism, Sedimentation veloc ity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogeni c intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine, These results demonstrate the feasib ility of using small molecules to stabilize the native fold of a poten tially 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 devel opment should prove useful for critically evaluating the amyloid hypot hesis-i.e., the putative cause-and-effect relationship between TTR amy loid deposition and the onset of familial amyloid polyneuropathy and s enile systemic amyloidosis.