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Novel Transthyretin Amyloid Fibril Formation Inhibitors: Synthesis, Biological Evaluation, and X-Ray Structural Analysis

机译:新型运甲状腺素蛋白淀粉样蛋白原纤维形成抑制剂:合成,生物学评估和X射线结构分析。

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摘要

Transthyretin (TTR) is one of thirty non-homologous proteins whose misfolding, dissocn., aggregation, and depositionis linked to human amyloid diseases. Previous studies have identified that TTR amyloidogenesis can be inhibitedthrough stabilization of the native tetramer state by small mol. binding to the thyroid hormone sites of TTR. We haveevaluated a new series of b-aminoxypropionic acids (compds. 5-21), with a single arom. moiety (aryl or fluorenyl)linked through a flexible oxime tether to a carboxylic acid. These compds. are structurally distinct from the nativeligand thyroxine and typical halogenated biaryl NSAID-like inhibitors to avoid off-target hormonal or anti-inflammatoryactivity. Based on an in vitro fibril formation assay, five of these compds. showed significant inhibition of TTRamyloidogenesis, with two fluorenyl compds. displaying inhibitor efficacy comparable to the well-known TTR inhibitordiflunisal. Fluorenyl 15 is the most potent compd. in this series and importantly does not show off-target antiinflammatoryactivity. Crystal structures of the TTR:inhibitor complexes, in agreement with mol. docking studies,revealed that the arom. moiety, linked to the sp2-hybridized oxime carbon, specifically directed the ligand in either aforward or reverse binding mode. Compared to the aryl family members, the bulkier fluorenyl analogs achieved moreextensive interactions with the binding pockets of TTR and demonstrated better inhibitory activity in the fibril formationassay. Preliminary optimization efforts are described that focused on replacement of the C-terminal acid in both thearyl and fluorenyl series (compds. 22-32). The compds. presented here constitute a new class of TTR inhibitors thatmay hold promise in treating amyloid diseases assocd. with TTR misfolding.
机译:运甲状腺素蛋白(TTR)是三十种非同源蛋白之一,其错误折叠,分解,聚集和沉积与人类淀粉样蛋白疾病有关。先前的研究已经确定,通过小摩尔稳定天然四聚体状态可以抑制TTR淀粉样蛋白生成。与TTR的甲状腺激素位点结合。我们评估了一个带有单个芳烃的新系列的b-氨基羟丙酸(化合物5-21)。通过柔性肟系链连接到羧酸上的部分(芳基或芴基)。这些compds。在结构上不同于天然配体甲状腺素和典型的卤代联芳基NSAID样抑制剂,以避免脱靶激素或抗炎活性。根据体外原纤维形成试验,其中五种构成。表现出显着抑制TTR淀粉样蛋白生成,有两个芴基化合物。显示出与众所周知的TTR抑制剂双氟尼醛相当的抑制剂功效。芴基15是最有效的化合物。在这个系列中,重要的是不显示脱靶抗炎活性。 TTR:抑制剂配合物的晶体结构与mol。对接研究,揭示了芳香。与sp2-杂化肟碳连接的部分,以正向或反向结合模式特异性地指导配体。与芳基家族成员相比,较大的芴基类似物与TTR的结合口袋实现了更广泛的相互作用,并在原纤维形成分析中表现出更好的抑制活性。描述了初步优化工作,这些工作着眼于取代芳基和芴基系列的C端酸(化合物22-32)。该compds。本文提出的是一类新的TTR抑制剂,有望在治疗淀粉样疾病相关疾病方面有希望。 TTR折叠错误。

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