High throughput screening for inhibitors of alpha-galactosidase.
High throughput screening for inhibitors of alpha-galactosidase.
复制标题
DOI：
10.2174/1875397301004010067
复制
发表时间：
2010-12-03
期刊：
影响因子：
--
通讯作者：
Zheng, Wei
中科院分区：
文献类型：
--
作者：
Motabar, Omid;Liu, Ke;Zheng, Wei
法布里病是一种罕见的由α -半乳糖苷酶a （GLA）缺乏引起的x -连锁溶酶体贮积症，该酶能催化鞘糖脂末端α -半乳糖基的水解，如globotriaosylneuroide （Gb3）。GLA基因中的许多突变是错义改变，导致该蛋白的错误折叠、稳定性降低和/或误转运。小分子化合物可以纠正错误折叠和错误运输，或激活突变酶，可能对治疗法布里病有用。我们使用人重组蛋白和纯化咖啡豆酶的制剂筛选了大约23万个化合物，以寻找该酶的激活剂和抑制剂。兰索拉唑被鉴定为从咖啡豆中提取的GLA的小分子抑制剂（IC(50) = 6.4 muM），但未发现对人GLA酶的抑制剂或激活剂。筛选结果表明，人GLA是一个难以被小分子抑制或激活的靶点。
Fabry disease is a rare X-linked lysosomal storage disorder caused by a deficiency in alpha-galactosidase A (GLA), which catalyzes the hydrolysis of terminal alpha-galactosyl groups from glycosphingolipids, such as globotriaosylceramide (Gb3). Many of the mutations in the GLA gene are missense alterations that cause misfolding, decreased stability, and/or mistrafficking of this protein. Small molecule compounds that correct the misfolding and mistrafficking, or activate the mutant enzyme, may be useful in the treatment of Fabry disease. We have screened a library of approximately 230,000 compounds using preparations of human recombinant protein and purified coffee bean enzyme in an effort to find activators and inhibitors of this enzyme. Lansoprazole was identified as a small molecule inhibitor of GLA derived from coffee beans (IC(50) = 6.4 muM), but no inhibitors or activators were identified for the human enzyme. The screening results indicate that human GLA is a difficult target for small molecule inhibition or activation.