Inhibition activities of iminosugars against glycoprotein processing

亚氨基糖对糖蛋白加工的抑制活性

基本信息

批准号：
22590059
负责人：
ADACHI Isao
金额：
$ 2.83万
依托单位：
University of Toyama
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590059/
关键词：
イミノ糖グリコシダーゼ光学異性体リソソーム病シャペロン

项目摘要

We studied the concise synthesis of DGJ and L-DGJ from L- and D-tagatose respectively in just four steps, and shows the value of the enantiomers of tagatose as chirons. As with other α-galactosidases L-DGJ was found to be an inhibitor of α-Gal A, about 1000-fold weaker than its enantiomer DGJ. L-DGJ was also found to be a chaperone for α-Gal A, again about 1000 times less active than DGJ. Non-competitive inhibition by L-DGJ is consistent with binding at a different site than DGJ which shows competitive inhibition and binds at the active site. While the inhibition of the same glycosidase by both enantiomers of an iminosugar is well-known, this is the first example of enantiomeric iminosugars acting as synergistic pharmacological chaperones for misfolded proteins; this result may indicate that binding at the active site of the enzyme is not necessary. There are many hundreds of pyrrolidine, piperidine and azepane sugar mimics but azetidines are only just beginning to be studied. There are few examples of carbohydratederived azetidines, although the properties of hydroxyazetidines are of current interest. N-Alkyl hydroxyazetidines are potent inhibitors of purine nucleoside phosphorylase with subnanomolar Ki. We studied the synthesis of an azetidine analogue of 6,7-diepicastanospermine and compares its glycosidase activity also with D-altronojirimycin.

我们仅在四个步骤中分别研究了L-和D-tagatose的DGJ和L-DGJ的简明合成，并显示了Tagatose作为Chirons的对映异构体的值。与其他α-半乳糖苷酶L-DGJ一样，发现是α-gal A的抑制剂，比其对映异构体DGJ弱约1000倍。还发现L-DGJ是α-GAL A的伴侣，再次比DGJ少1000倍。 L-DGJ的非竞争性抑制与与DGJ不同的位点的结合一致，DGJ在活性位点显示竞争性抑制和结合。虽然两种映体映体对同一糖苷酶的抑制是众所周知的，但这是对映体iminosugars的第一个例子，它是错误折叠蛋白的协同药物链酮。该结果可能表明在酶的活性位点结合是不需要的。有数百种吡咯烷，哌啶和阿兹ep糖糖模拟物，但偶氮丁丁才刚刚开始研究。尽管羟基苯胺的性质具有目前的意义，但很少有碳化偶氮丁丁的例子。 N-烷基羟基苯胺是用亚洋摩尔Ki的纯核磷酸化酶的潜在抑制剂。我们研究了6,7-Diepicastanospermine的氮杂氨酸类似物的合成，并将其糖苷酶活性与D-α-α-甲二霉素进行了比较。