Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein
Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein
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DOI：
10.1016/j.bmcl.2017.04.062
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发表时间：
2017-06-15
影响因子：
2.7
通讯作者：
Ohgane, Kenji
中科院分区：
文献类型：
--
作者：
Fukuda, Hiromitsu;Karaki, Fumika;Ohgane, Kenji
C型尼曼-匹克病是一种致命的进行性神经退行性疾病，主要由C1型尼曼-匹克病（NPC 1）突变引起，NPC 1是一种晚期内体膜蛋白，对细胞内胆固醇转运至关重要。最常见的突变I1061 T（Ile到Thr）干扰蛋白质折叠过程。因此，突变但固有功能的NPC 1蛋白通过蛋白酶体过早降解，导致NPC 1功能丧失。以前，我们报道了甾醇衍生物作为NPC 1的药理学伴侣，并表明这些衍生物可以通过直接结合和稳定蛋白质来使I1061 T NPC 1突变体的折叠缺陷表型正常化。在这里，我们报告了一系列的化合物含有菲啶-6-酮支架作为第一类的非甾体药理学伴侣NPC 1。我们还研究了它们的构效关系。(C)2017爱思唯尔有限公司版权所有
Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships. (C) 2017 Elsevier Ltd. All rights reserved.