Eeyarestatin I

Eeyarestatin I（EerI [1]）是内质网相关性降解（ERAD）抑制剂，扰乱内质网（ER）体内平衡，并具有类似于Bortezomib的抗肿瘤活性。ESI诱导JEKO-1细胞死亡，IC50值为4±1.2 μM[2]。ESI也是蛋白质转运的有效抑制剂。ESI对ER转运和N-糖基化的体外IC50值约为70 μM[1]。

ERAD途径可以清除错误折叠的ER蛋白质，及时从ER中清理错误折叠的蛋白，能维持ER稳态[2]。N-糖基化是最常见的和多功能的蛋白质修饰，作用于Asn-Xaa-Ser/Thr sequon天冬酰胺的β酰胺键上。ER甘露糖苷酶I可能引发折叠不当的糖蛋白靶向降解[4]。

在A9细胞中，与Me2SO相比，EerI使多泛素化的MHC I类分子重链（HC）蛋白在细胞质中积累。与MG132相比， EerI导致细胞生成极少量的去泛素化去糖基化HC分子，尽管此数量与积累的多泛素化HC数量接近[5]。在H1299细胞中，与对照相比，连续24小时给予EerI显著（P < 0.01）减少细胞增殖（24.0％）[6]。

在无胸腺裸鼠中，皮下注射Matrigel与H1299细胞（8×106）后的第2天和第6天给予10 μM的EerI，与DMSO对照组相比，EerI显著减少肿瘤的生长[6]。

参考文献：
[1].  Benedict C. S. Cross, Craig McKibbin, Anna C. Callan, et al. Eeyarestatin I inhibits Sec61-mediated protein translocation at the endoplasmic reticulum. Journal of Cell Science, 2009, 122:4393-4400.
[2]. Qiuyan Wang, Bidhan A. Shinkre, Jin-gu Lee, et al. The ERAD Inhibitor Eeyarestatin I Is a Bifunctional Compound with a Membrane-Binding Domain and a
p97/VCP Inhibitory Group. PLoS ONE, 2010, 5(11):e15479.
[3].  Shifra Ben-Dor, Nir Esterman, Eitan Rubin, et al. Biases and complex patterns in the residues flanking protein N-glycosylation sites. Glycobiology, 2004, 14(2):95-101.
[4].  Myriam Ermonval, Claudia Kitzmüller, Anne Marie Mir, et al. N-glycan structure of a short-lived variant of ribophorin I expressed in the MadIA214 glycosylation-defective cell line reveals the role of a mannosidase that is not ER mannosidase I in the process of glycoprotein degradation. Glycobiology, 2001, 11(7):565-576.
[5].  Qiuyan Wang, Lianyun Li and Yihong Ye. Inhibition of p97-dependent Protein Degradation by Eeyarestatin I. Journal of Biological Chemistry, 2008, 283(12):7445-7454.
[6].  Christopher W. Valle, Taehong Min, Manish Bodas, et al. Critical Role of VCP/p97 in the Pathogenesis and Progression of Non-Small Cell Lung Carcinoma. PLoS ONE, 2011, 6(12): e29073.