Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2
Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2
复制标题
增强与进行性家族性肝内胆汁淤积 2 型相关的胆汁盐输出泵突变体转运活性的小分子的发现和结构开发
DOI：
10.1016/j.bmc.2012.03.016
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Misawa T.
中科院分区：
文献类型：
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作者：
張宇;岩田達也;山元淳平;人見研一;岩井成憲;藤堂剛;E.D.Getzoff;神取秀樹;Misawa T.
进行性家族性肝内胆汁淤积2型（PFIC2）是由胆盐输出泵（BSEP）的遗传突变引起的，如E297G BSEP，这是一种折叠缺陷突变，不能运输到内质网（ER）之外。4-苯基丁酸（4-PBA）可增强E297G BSEP的细胞表面表达和转运能力，但需要较高的剂量（1mM以上）才能显示效果。在这里，我们发现胆汁酸可能作为药物伴侣，促进E297G BSEP的适当折叠和运输。我们还描述了对E297G BSEP具有有效药理伴侣活性的非甾体化合物的发现和结构开发。
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by hereditary mutations of bile salt export pump (BSEP), such as E297G BSEP, which is a folding-defective mutant that is unable to traffic beyond the endoplasmic reticulum (ER). 4-Phenylbutyric acid (4-PBA) enhances the cell surface expression and transport capacity of E297G BSEP, but has a relatively high dose (1mM or more) is required to show the effect. Here, we show that bile acids possibly act as pharmacological chaperones, promoting the proper folding and trafficking of E297G BSEP. We also describe the discovery and structural development of non-steroidal compounds with potent pharmacological chaperone activity for E297G BSEP.