Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments.,Journal of Medicinal Chemistry

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Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-11 , DOI: 10.1021/acs.jmedchem.0c00934
Takeshi Yokoyama ₁ , Mineyuki Mizuguchi ₁

Affiliation

Transthyretin (TTR) is a homotetrameric protein in human plasma. The dissociation of the TTR tetramer and misfolding of the TTR monomer result in the formation of amyloid fibrils. Hereditary TTR amyloidosis is characterized by the extracellular deposition of amyloid fibrils containing TTR variants. The development of small molecules that kinetically stabilize the TTR tetramer is one of the effective strategies for the treatment of hereditary TTR amyloidosis. So far, several stabilizers have been discovered. Tafamidis is the only approved stabilizer for treatment of hereditary TTR amyloidosis, although two nucleic acid medicines that inhibit TTR synthesis, inotersen and patisiran, were recently approved for treatment of this disorder. In this Perspective, we seek to describe the representative kinetic stabilizers from discovery to development, interweaving the crystallographic study of the complex structures.

中文翻译：

运甲状腺素蛋白淀粉样生成抑制剂：从发现到目前的发展。

运甲状腺素蛋白（TTR）是人血浆中的同四聚体蛋白。TTR四聚体的解离和TTR单体的错误折叠导致淀粉样蛋白原纤维的形成。遗传性TTR淀粉样变性病的特征是含有TTR变异体的淀粉样蛋白原纤维在细胞外沉积。在动力学上稳定TTR四聚体的小分子的开发是治疗遗传性TTR淀粉样变性的有效策略之一。到目前为止，已经发现了几种稳定剂。尽管最近批准了两种抑制TTR合成的核酸药物inotersen和patisiran，Tafamidis是唯一被批准用于治疗遗传性TTR淀粉样变性的稳定剂，但该药物已被批准用于治疗该疾病。在这个观点中，我们试图描述从发现到发展的代表性动力学稳定剂，

更新日期：2020-09-11

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