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Grassystatins D–F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer
Journal of Natural Products ( IF 5.1 ) Pub Date : 2017-10-31 00:00:00 , DOI: 10.1021/acs.jnatprod.7b00551
Fatma H. Al-Awadhi , Brian K. Law 1 , Valerie J. Paul 2 , Hendrik Luesch
Affiliation  

Three new modified peptides named grassystatins D–F (13) were discovered from a marine cyanobacterium from Guam. Their structures were elucidated using NMR spectroscopy and mass spectrometry. The hallmark structural feature in the peptides is a statine unit, which contributes to their aspartic protease inhibitory activity preferentially targeting cathepsins D and E. Grassystatin F (3) was the most potent analogue, with IC50 values of 50 and 0.5 nM against cathepsins D and E, respectively. The acidic tumor microenvironment is known to increase the activation of some of the lysosomal proteases associated with tumor metastasis such as cathepsins. Because cathepsin D is a biomarker in aggressive forms of breast cancer and linked to poor prognosis, the effects of cathepsin D inhibition by 1 and 3 on the downstream cellular substrates cystatin C and PAI-1 were investigated. Furthermore, the functional relevance of targeting cathepsin D substrates was evaluated by examining the effect of 1 and 3 on the migration of MDA-MD-231 cells. Grassystatin F (3) inhibited the cleavage of cystatin C and PAI-1, the activities of their downstream targets cysteine cathepsins and tPA, and the migration of the highly aggressive triple negative breast cancer cells, phenocopying the effect of siRNA-mediated knockdown of cathepsin D.

中文翻译:

Grassystatins D–F,来自海洋蓝细菌的有效天冬氨酸蛋白酶抑制剂,可作为针对浸润性乳腺癌的潜在抗转移药

名为草抑制素三种新的修饰肽D-F(1 - 3)从关岛海洋蓝藻被发现。使用NMR光谱法和质谱法阐明了它们的结构。肽的标志性结构特征是他汀类单元,有助于其优先针对组织蛋白酶D和E的天冬氨酸蛋白酶抑制活性。格拉斯他汀F(3)是最有效的类似物,IC 50对组织蛋白酶D和E的值分别为50和0.5nM。已知酸性肿瘤微环境会增加某些与肿瘤转移有关的溶酶体蛋白酶(例如组织蛋白酶)的活化。由于组织蛋白酶D是侵袭性乳腺癌的一种生物标志物,并且与不良预后相关,因此研究了组织蛋白酶D抑制13对下游细胞底物胱抑素C和PAI-1的作用。此外,通过检查13对MDA-MD-231细胞迁移的影响,评估了靶向组织蛋白酶D底物的功能相关性。草地抑素F(3)抑制胱抑素C和PAI-1的切割,其下游靶标半胱氨酸组织蛋白酶和tPA的活性以及高度侵袭性的三阴性乳腺癌细胞的迁移,表型证明了siRNA介导的组织蛋白酶D敲除的作用。
更新日期:2017-10-31
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