Arginine modification of lycosin-I to improve inhibitory activity against cancer cells,Organic & Biomolecular Chemistry

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Arginine modification of lycosin-I to improve inhibitory activity against cancer cells
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2017-10-12 00:00:00 , DOI: 10.1039/c7ob02233f
Peng Zhang _{1,

2,

3,

4,

5} , Jing Ma _{3,

5,

6,

7} , Yujie Yan _{1,

2,

3,

4,

5} , Bo Chen _{1,

2,

3,

4,

5} , Bobo Liu _{3,

5,

6,

7} , Cui Jian _{3,

5,

6,

7} , Baode Zhu _{1,

2,

3,

4,

5} , Songping Liang _{1,

2,

3,

4,

5} , Youlin Zeng _{3,

5,

6,

7} , Zhonghua Liu _{1,

2,

3,

4,

5}

Affiliation

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.

中文翻译：

lycosin-I的精氨酸修饰可提高对癌细胞的抑制活性

Lycosin-I是一种线性结构的两亲性α-螺旋抗癌肽（ACP），它是从蜘蛛莱科萨（Lycosa singoriensis）提取的可以激活线粒体死亡途径，诱导肿瘤细胞凋亡，并上调p27抑制细胞增殖。然而，溶血素-I作为新型抗癌药的适用性受到其低细胞进入和在实体瘤中的功效的限制。氨基酸取代为提高ACP的抗癌活性和生物利用度提供了有效而适度的策略。本文中，通过用赖氨酸（Lys）替换为精氨酸（Arg）来设计和合成精氨酸修饰的lycosin-I（称为R-lycosin-I）。该肽对溶瘤细胞的抗癌活性和穿透性均高于溶血素-1。他们的理化特性包括二级结构，流体动力学尺寸和ζ电势均显示出明显差异。荧光分析已经证实，R-lycosin-I表现出增加的细胞摄取和改善的细胞内分布。由于其优异的理化特性和较高的血清稳定性，R-lycosin-I可以深入渗透到肿瘤球体中，并在3D肿瘤模型中产生强毒性。总体而言，这些发现表明，精氨酸修饰可为改善lycosin-I的抗癌活性提供有效的策略，而R-lycosin-I可能是开发抗癌药物的有用线索。

更新日期：2017-11-15

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