Sanches Paulo R S, Carneiro Bruno M, Batista Mariana N, Braga Ana Cláudia S, Lorenzón Esteban N, Rahal Paula, Cilli Eduardo Maffud
Department of Biochemistry and Chemical Technology, Institute of Chemistry, UNESP, Univ Estadual Paulista, Araraquara, SP, CEP 14800-060, Brazil.
Amino Acids. 2015 Jul;47(7):1433-43. doi: 10.1007/s00726-015-1980-7. Epub 2015 Apr 14.
Conjugate compounds constitute a new class of molecules of important biological interest mainly for the treatment of diseases such as cancer. The N-terminus region of cationic peptides has been described as important for their biological activity. The aim of this study was to evaluate the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and the effect of conjugating this macromolecule with gallic acid (C7H6O5) in terms of structure, anti-cancer activity, and toxicity. An N-terminus GA-Hecate peptide conjugate was synthesized to provide information regarding the relationship between the amino-terminal region and its charge and the secondary structure and biological activity of the peptide; and the effects of gallic acid on these parameters. Peptide secondary structure was confirmed using circular dichroism (CD). The CD measurements showed that the peptide has a high incidence of α-helical structures in the presence of SDS and LPC, while GA-Hecate presented lower incidence of α-helical structures in the same chemical environment. An evaluation of the anti-cancer activity in HeLa cancer cells indicated that both peptides are active, but that coupling gallic acid at the N-terminus decreased the activity of the free peptide. GA-Hecate showed lower activity in non-tumor keratinocyte cells but higher hemolytic activity. Our findings suggest that the N-terminus of Hecate plays an important role in its activity against cervical cancer by affecting it secondary structure, toxicity, and hemolytic activity. This study highlights the importance of the N-terminus in antitumor activity and could provide an important tool for developing new anti-cancer drugs.
共轭化合物构成了一类具有重要生物学意义的新型分子，主要用于治疗癌症等疾病。阳离子肽的N端区域已被描述为对其生物活性至关重要。本研究的目的是评估裂解肽赫卡特（FALALKALKKALKKLKKALKKAL）以及将该大分子与没食子酸（C7H6O5）共轭在结构、抗癌活性和毒性方面的影响。合成了一种N端GA-赫卡特肽共轭物，以提供有关氨基末端区域与其电荷之间的关系以及肽的二级结构和生物活性的信息；以及没食子酸对这些参数的影响。使用圆二色性（CD）确认肽的二级结构。CD测量表明，在SDS和LPC存在的情况下，该肽具有高发生率的α-螺旋结构，而GA-赫卡特在相同化学环境中α-螺旋结构的发生率较低。对HeLa癌细胞的抗癌活性评估表明，两种肽均具有活性，但在N端偶联没食子酸会降低游离肽的活性。GA-赫卡特在非肿瘤角质形成细胞中显示出较低的活性，但具有较高的溶血活性。我们的研究结果表明，赫卡特的N端通过影响其二级结构、毒性和溶血活性，在其抗宫颈癌活性中发挥重要作用。本研究突出了N端在抗肿瘤活性中的重要性，并可为开发新的抗癌药物提供重要工具。
