Potent and Selective Structure-Based Dibenzofuran Inhibitors of Transthyretin Amyloidogenesis:  Kinetic Stabilization of the Native State

作者：H. Michael Petrassi, Steven M. Johnson, Hans E. Purkey, Kyle P. Chiang, Traci Walkup, Xin Jiang, Evan T. Powers, Jeffery W. Kelly · 发表于：Journal of the American Chemical Society · 年份：2005 · DOI：10.1021/ja044351f · 被引用次数：77 · 研究领域：Amyloidosis: Diagnosis, Treatment, Outcomes、Protein Kinase Regulation and GTPase Signaling、Alzheimer's disease research and treatments

Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1). An X-ray cocrystal structure of TTR.1(2) reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employed to append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramatically increased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on the native tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions. Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to ameliorate disease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventing the onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclear which of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enables these inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma, required...