Zhang Peng, Ma Jing, Yan Yujie, Chen Bo, Liu Bobo, Jian Cui, Zhu Baode, Liang Songping, Zeng Youlin, Liu Zhonghua
The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Org Biomol Chem. 2017 Nov 15;15(44):9379-9388. doi: 10.1039/c7ob02233f.
Lycosin-I is a linear amphipathic α-helical anticancer peptide (ACP) extracted from the spider Lycosa singoriensis, which can activate the mitochondrial death pathway to induce apoptosis in tumor cells and up-regulate p27 to inhibit cell proliferation. However, the applicability of lycosin-I as a novel anticancer drug is limited by its low cellular entry and efficacy in solid tumors. Amino acid substitution presents an effective and modest strategy to improve the anticancer activity and bioavailability of ACPs. Herein, an arginine-modified lycosin-I (named R-lycosin-I) was designed and synthesized by substituting lysine (Lys) with arginine (Arg). This peptide exhibited higher anticancer activity and penetrability against solid tumor cells than lycosin-I. They displayed noticeable differences in their physicochemical properties including the secondary structure, hydrodynamic size, and zeta potential. Fluorescence analyses have confirmed that R-lycosin-I exhibits increased cellular uptake and improved intracellular distribution. Due to its superior physical and chemical properties and high serum stability, R-lycosin-I could penetrate deeply into tumor spheroids and produce strong toxicity in the 3D tumor model. Overall, these findings suggest that arginine modification may provide an effective strategy for improving the anticancer activity of lycosin-I, and R-lycosin-I may be a useful lead for developing anticancer drugs.
狼蛛素-I是一种从中华狼蛛中提取的线性两亲性α-螺旋抗癌肽（ACP），它可以激活线粒体死亡途径，诱导肿瘤细胞凋亡，并上调p27以抑制细胞增殖。然而，狼蛛素-I作为一种新型抗癌药物的适用性受到其低细胞摄取率和在实体瘤中的疗效的限制。氨基酸取代是一种有效且适度的策略，可提高抗癌肽的抗癌活性和生物利用度。在此，通过用精氨酸（Arg）取代赖氨酸（Lys），设计并合成了一种精氨酸修饰的狼蛛素-I（命名为R-狼蛛素-I）。该肽对实体瘤细胞表现出比狼蛛素-I更高的抗癌活性和穿透性。它们在包括二级结构、流体动力学尺寸和zeta电位在内的物理化学性质上表现出明显差异。荧光分析证实，R-狼蛛素-I表现出增加的细胞摄取和改善的细胞内分布。由于其优异的物理化学性质和高血清稳定性，R-狼蛛素-I可以深入穿透肿瘤球体，并在三维肿瘤模型中产生强烈的毒性。总体而言，这些发现表明精氨酸修饰可能为提高狼蛛素-I的抗癌活性提供一种有效策略，并且R-狼蛛素-I可能是开发抗癌药物的有用先导物。
