Petrassi H Michael, Johnson Steven M, Purkey Hans E, Chiang Kyle P, Walkup Traci, Jiang Xin, Powers Evan T, Kelly Jeffery W
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC265, La Jolla, CA 92037, USA.
J Am Chem Soc. 2005 May 11;127(18):6662-71. doi: 10.1021/ja044351f.
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 for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-based amyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates for further pharmacologic evaluation.
转甲状腺素蛋白（TTR）的淀粉样变形成需要限速的四聚体解离和部分单体变性，以产生能够错误组装的物种。这个过程通过浊度监测来鉴定转甲状腺素蛋白淀粉样变形成抑制剂，包括二苯并呋喃-4,6-二羧酸（1）。TTR.1(2)的X射线共晶体结构表明，它仅利用两个甲状腺素结合口袋的外部来结合并抑制TTR淀粉样变形成。在此，采用基于结构的设计在二苯并呋喃环的C1处连接芳基取代基，以补充甲状腺素结合口袋未使用的内部。由此得到了28种效力增强且血浆TTR结合选择性显著提高的淀粉样变形成抑制剂。它们的作用机制是对TTR的天然四聚体结构施加动力学稳定作用，形成在生理条件下无法逾越的屏障。由于已知通过等位基因间反式抑制对TTR天然状态进行动力学稳定可改善疾病，因此有理由乐观地认为基于二苯并呋喃的抑制剂也会有同样效果。预防淀粉样变形成的发生是临床上最保守的干预策略，因为目前尚不清楚TTR错误组装中间体中的哪一种会导致毒性。这种特殊的结合选择性使这些抑制剂能够在诸如血浆这样的复杂生物流体中占据甲状腺素结合位点，这是抑制人类淀粉样变形成所必需的。现已证实，基于二苯并呋喃的淀粉样变形成抑制剂具有高选择性、亲和力和效力，因此是进一步进行药理学评估的优秀候选药物。
