Drug discovery targeted at transthyretin cardiac amyloidosis: rational design, synthesis, and biological activity of new transthyretin amyloid inhibitors

We have previously designed and synthesized ligands that stabilize the transthyretin (TTR) tetramer, in order to obtain therapeutically active compounds for familial amyloid polyneuropathy. We are hereby reporting a drug design strategy to optimize these ligands to target familial amyloid cardiomyopathy, through the following steps: (a) Structure Activity Relationship (SAR) analyses of the ligands described previously for the TTR tetramer, classified in structurally similar families; (b) drug design/optimization of TTR ligands through docking in the TTR tetramer three-dimensional structure and through optimization of physicochemical/pharmacokinetic/selectivity properties; (c) comparative structural analyses of selected amyloidogenic and non-amyloidogenic TTR mutants and native TTR structures; and (d) virtual screening of commercially available ligands and therapeutically active compounds (repurposing) towards wild-type and mutant TTR tetramer structures. First results in steps (a) and (d) of this strategy will be reported.