Julius Richard L, Hawthorne M Frederick
University of California, Los Angeles, California, USA.
Drug News Perspect. 2008 Jun;21(5):258-66. doi: 10.1358/dnp.2008.21.5.1219011.
Misfolding and subsequent aggregation of any of a number of proteins leads to the accumulation of amyloid fibrils, which have been associated with a variety of diseases. One such amyloidogenic protein is transthyretin (TTR), a 55-kDa homotetrameric protein found in the blood plasma and cerebrospinal fluid where it binds and transports thyroxine. In humans, the T119M-TTR variant has been shown to be protective against familial amyloid polyneuropathy, a TTR amyloid disease, through kinetic stabilization of the unliganded tetrameric structure. Studies have indicated that a diverse range of small molecules may also bind TTR in the thyroxine-binding pocket and subsequently kinetically stabilize the protein's native conformation in vitro, preventing the misfolding that has been implicated in the progression of several diseases. However, cyclooxygenase inhibition is a common unwanted side effect among such small-molecule kinetic stabilizers. The recent development of transthyretin stabilizers not subject to cyclooxygenase inhibition may prove attractive for the long-term treatment of TTR misfolding diseases in humans. Such compounds are attained by incorporating aromatic carborane icosahedra at strategic points in their structures.
多种蛋白质中的任何一种发生错误折叠并随后聚集会导致淀粉样纤维的积累，而淀粉样纤维与多种疾病相关。一种这样的淀粉样蛋白生成蛋白是转甲状腺素蛋白（TTR），它是一种55千道尔顿的同四聚体蛋白，存在于血浆和脑脊液中，在那里它结合并运输甲状腺素。在人类中，T119M - TTR变体已被证明通过未结合配体的四聚体结构的动力学稳定作用，对家族性淀粉样多神经病（一种TTR淀粉样疾病）具有保护作用。研究表明，多种小分子也可能在甲状腺素结合口袋中与TTR结合，并随后在体外动力学稳定该蛋白的天然构象，防止与几种疾病进展相关的错误折叠。然而，环氧合酶抑制是这类小分子动力学稳定剂常见的不良副作用。最近开发的不受环氧合酶抑制的转甲状腺素蛋白稳定剂可能对人类TTR错误折叠疾病的长期治疗具有吸引力。这类化合物是通过在其结构的关键位置引入芳香碳硼烷二十面体而获得的。
