Grassypeptolides as natural inhibitors of dipeptidyl peptidase 8 and T-cell activation.
Grassypeptolides as natural inhibitors of dipeptidyl peptidase 8 and T-cell activation.
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DOI：
10.1002/cbic.201300762
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发表时间：
2014-04-14
期刊：
影响因子：
3.2
通讯作者：
Luesch, Hendrik
中科院分区：
文献类型：
--
作者：
Kwan, Jason C.;Liu, Yanxia;Ratnayake, Ranjala;Hatano, Ryo;Kuribara, Akiko;Morimoto, Chiko;Ohnuma, Kei;Paul, Valerie J.;Ye, Tao;Luesch, Hendrik
由海洋蓝细菌产生的天然产物通常是高度修饰的肽和缩肽，其具有作为蛋白酶抑制剂的潜力。为了发现新的蛋白酶抑制活性和选择性，针对一组蛋白酶筛选草肽内酯A（1），发现其选择性抑制DPP 8超过DPP 4。还发现草肽内酯抑制活化的T细胞中的IL-2产生和增殖，这与DPP 8在免疫系统中的假定作用一致。Jurkat细胞中也观察到了这些效应，并且证明草肽内酯可抑制Jurkat细胞胞质溶胶中的DPP活性。在计算机对接建议两种可能的结合模式的grassypeptolides -无论是在活性位点的DPP 8和在一个入口的内部空腔。总的来说，这些结果表明，草肽内酯可能是有用的工具化合物在DPP 8功能的研究。
Natural products made by marine cyanobacteria are often highly modified peptides and depsipeptides that have the potential to act as inhibitors for proteases. In the interest of finding novel protease inhibition activity and selectivity grassypeptolide A (1) was screened against a panel of proteases and found to selectively inhibit DPP8 over DPP4. Grassypeptolides were also found to inhibit IL-2 production and proliferation in activated T-cells, consistent with a putative role of DPP8 in the immune system. These effects were also observed in Jurkat cells, and DPP activity in Jurkat cell cytosol was shown to be inhibited by grassypeptolides. In silico docking suggests two possible binding modes of grassypeptolides – both at the active site of DPP8 and at one of the entrances to the internal cavity. Collectively these results suggest that grassypeptolides may be useful tool compounds in the study of DPP8 function.
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