Rational design of potent human transthyretin amyloid disease inhibitors

The human amyloid disorders, familiar amyloid polyneuropathy, familial amyl oid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and he art tissue. Several nonsteroidal anti-inflammatory drugs and structurally s imilar compounds have been found to strongly inhibit the formation of TTR a myloid fibrils in vitro, These include flufenamic acid, diclofenac, flurbip rofen, and resveratrol. Crystal structures of the protein-drug complexes ha ve been determined to allow detailed analyses of the protein-drug interacti ons that stabilize the native tetrameric conformation of TTR and inhibit th e formation of amyloidogenic TTR. Using a structure-based drug design appro ach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethyl phenyl) phenoxazine 4,6-dicarboxylic acid have been discovered to be very p otent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associ ated amyloid diseases.