Structural stabilization of transthyretin by a new compound,6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione

Familial amyloid polyneuropathy (fap) is a genetic,adult-onset,neurodegenerative disorder caused by amyloid formation of transthyretin (ttr),a thyroxine-binding protein. mutation in ttr causes a propensity of ttr tetramer to dissociate to monomer,which is the first step to amyloidosis. thus,a drug that can stabilize the tetramer structure will have therapeutic benefit. here,by virtual screening and biochemical assays,we identified small molecule 6-benzoyl-2-hydroxy-1h-benzo[de]isoquinoline-1,3(2h)-dione (l6) that can prevent the dissociation of ttr to monomer. x-ray crystallography reveals that l6 binds to the t4 binding pocket of ttr. these findings show that l6 is a candidate ttr stabilizer. © 2015 japanese pharmacological society.