A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity.

ABSTRACT: Transthyretin aggregation-associated proteotoxicity appears to cause several human amyloid diseases. Rate-limiting tetramer dissociation and monomer misfolding of transthyretin (TTR) occur before its aggregation into cross-beta-sheet amyloid fibrils. Small molecule binding to and preferential stabilization of the tetrameric state of TTR over the dissociative transition state raises the kinetic barrier for dissociation, imposing kinetic stabilization on TTR and preventing aggregation. This is an effective strategy to halt neurodegeneration associated with polyneuropathy, according to recent placebo-controlled clinical trial results. In three recent papers, we systematically ranked possibilities for the three substructures composing a typical TTR kinetic stabilizer, using fibril inhibition p

SUBMITTER: Choi S 

PROVIDER: S-EPMC2818972 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature