新型人工分枝抗菌肽的选择性抗肿瘤作用及其机制研究

项目名称： 新型人工分枝抗菌肽的选择性抗肿瘤作用及其机制研究

项目编号： No.81502618

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 黄圆

作者单位： 浙江省肿瘤医院

项目金额： 18.5万元

中文摘要： 阳离子两亲性抗菌肽的抗肿瘤作用逐渐被人们认识并成为新兴研究热点。不同于传统天然抗菌肽及其片段的研究，本课题前期自行设计合成一系列具有(XXYY)n框架结构的新型人工抗菌肽，并在线性抗菌肽(LLKK)4基础上进一步结构优化设计双臂分枝多肽[(LLKK)2]2κC及四臂星形样多肽{[(LLKK)2]2κC}2，该分支多肽既保有线性多肽(LLKK)4的广谱抗菌活性又相对增强了其生物相容性，同时研究发现该分枝多肽还存在选择性抗肿瘤活性，即杀伤肿瘤细胞的同时不损伤正常组织细胞。因此，本项目将深入研究人工分枝抗菌肽[(LLKK)2]2κC 、{[(LLKK)2]2κC}2的体内外选择性抗肿瘤作用，并阐明该分枝多肽诱导细胞发生的生物学行为，涉及细胞膜裂解、凋亡、自噬及细胞骨架损伤，以期探讨可能的作用机制。该研究为当前抗菌肽的研究提供了新的思路，并有望为临床肿瘤治疗提供新的途径和希望。

中文关键词： 分枝抗菌肽；选择性；抗肿瘤活性；膜裂解

英文摘要： Recently, cationic amphiphilic antimicrobial peptides have been recognized as potential candidates for cancer treatment. Different from former researches on traditional natural antimicrobial peptides and their fragments, we previously have rationally designed a novel class of antimicrobial peptide (XXYY)n, and based on linear (LLKK)4, [(LLKK)2]2κC (2-arm branched peptide) and {[(LLKK)2]2κC}2 (4-arm starlike peptide) were further developed which possess similarly potent antimicrobial activities against a broad spectrum of bacteria and improved biocompatibility. Meawhile, these peptides are toxic to cancer cells but not to normal mammalian cells , exhibit selective cytotoxicity against cancer cells. In this study, we will further evaluate their selective antitumor activities in vitro and in vivo, and study the underlying mechanisms of action including cell membrane lysis, apoptosis, autophagy and cytoskeletal disruption. Taken together, this study may provide fundamental support for further therapeutic application of antimicrobial peptides as potential antitumor agent.

英文关键词： Branched antimicrobial peptides; selectivity; Antitumor activity;membrane lysis