Kempopeptin C, a Novel Marine-Derived Serine Protease Inhibitor Targeting Invasive Breast Cancer.
Kempopeptin C, a Novel Marine-Derived Serine Protease Inhibitor Targeting Invasive Breast Cancer.
复制标题
DOI：
10.3390/md15090290
复制
发表时间：
2017-09-16
期刊：
影响因子：
5.4
通讯作者：
Luesch H
中科院分区：
文献类型：
--
作者：
Al-Awadhi FH;Salvador LA;Law BK;Paul VJ;Luesch H
Kempopeptin C是一种新型的Kempopeptin B的氯化类似物，从佛罗里达州Kemp海峡收集的海洋蓝藻中发现。用核磁共振谱和质谱对其结构进行了分析。靠近3-氨基-6-羟基-2-哌酮（Ahp）部分n端的碱性赖氨酸残基的存在有助于其对胰蛋白酶和相关蛋白酶的选择性。kempopeptin C对胰蛋白酶、纤溶酶和基质酶的抑制作用，IC50分别为0.19、0.36和0.28 μM。由于这些蛋白酶在癌症进展和转移中的重要性，以及它们在靶向重叠底物方面的功能冗余，我们研究了kempopeptin C对基质酶下游细胞底物CDCP1和desmoglin -2 （Dsg-2）的影响。Kempopeptin C在体外可抑制这两种底物的裂解。此外，kempopeptin C可降低MDA-MB-231细胞中CDCP1的切割至10µM。通过评估kempopeptin C对乳腺癌细胞迁移的影响，探讨靶向基质酶及相关蛋白酶的功能相关性。Kempopeptin C对侵袭性MDA-MB-231细胞在10µM和20µM下的迁移能力分别有37%和60%的抑制作用。
Kempopeptin C, a novel chlorinated analogue of kempopeptin B, was discovered from a marine cyanobacterium collected from Kemp Channel in Florida. The structure was elucidated using NMR spectroscopy and mass spectrometry (MS). The presence of the basic Lys residue adjacent to the N-terminus of the 3-amino-6-hydroxy-2-piperidone (Ahp) moiety contributed to its selectivity towards trypsin and related proteases. The antiproteolytic activity of kempopeptin C was evaluated against trypsin, plasmin and matriptase and found to inhibit these enzymes with IC50 values of 0.19, 0.36 and 0.28 μM, respectively. Due to the significance of these proteases in cancer progression and metastasis, as well as their functional redundancy with respect to targeting overlapping substrates, we examined the effect of kempopeptin C on the downstream cellular substrates of matriptase: CDCP1 and desmoglein-2 (Dsg-2). Kempopeptin C was shown to inhibit the cleavage of both substrates in vitro. Additionally, kempopeptin C reduced the cleavage of CDCP1 in MDA-MB-231 cells up to 10 µM. The functional relevance of targeting matriptase and related proteases was investigated by assessing the effect of kempopeptin C on the migration of breast cancer cells. Kempopeptin C inhibited the migration of the invasive MDA-MB-231 cells by 37 and 60% at 10 and 20 µM, respectively.
登录
查看更多内容
Desmoglein 2是胰腺癌中Kallikrein 7的底物。
影响因子：
3.8
作者：
Ramani VC;Hennings L;Haun RS
通讯作者：
Haun RS
影响因子：
2.1
作者：
Bonjouklian, R;Smitka, TA;Patterson, GML
通讯作者：
Patterson, GML
影响因子：
5.6
作者：
Farady, Christopher J.;Sun, Jeonghoon;Craik, Charles S.
通讯作者：
Craik, Charles S.
影响因子：
8
作者：
Law, M. E.;Corsino, P. E.;Jahn, S. C.;Davis, B. J.;Chen, S.;Patel, B.;Pham, K.;Lu, J.;Sheppard, B.;Norgaard, P.;Hong, J.;Higgins, P.;Kim, J-S;Luesch, H.;Law, B. K.
通讯作者：
Law, B. K.
影响因子：
8
作者：
Bhatt, AS;Erdjument-Bromage, H;Moasser, MM
通讯作者：
Moasser, MM