抗癌stapled D型多肽的结构优化及其体内靶向递送研究

项目名称： 抗癌stapled D型多肽的结构优化及其体内靶向递送研究

项目编号： No.81473149

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陆伟跃

作者单位： 复旦大学

项目金额： 100万元

中文摘要： 多肽类p53蛋白激活剂由于具有高亲和力和高专一性的特点一直是该领域的研究热点，但常规L型多肽的稳定性差和跨膜转运能力弱制约着此类激活剂的发展。本课题拟通过D型多肽和stapled策略并结合肿瘤靶向递送技术，解决和改善多肽类激活剂的体内稳定性和递送问题，实现并提高其体内抗肿瘤作用，推动多肽类激活剂的研究发展。课题采用D型多肽改造提高多肽激活剂耐受酶解的能力，从而提升其生物稳定性；stapled多肽策略增加多肽的透细胞膜能力，从而改善多肽的细胞内递送；RGD修饰的肿瘤靶向递药系统提高多肽的体内肿瘤组织靶向能力。通过多技术多层面的结合，优化多肽类激活剂的体内药效。

中文关键词： p53蛋白激活剂；stapled；D型多肽；结构优化；MDM2/MDMX；肿瘤靶向递送

英文摘要： Peptide activator of tumor suppressor p53 with high affinity and specificity has been characterized hotspot in the field. However, poor stability and cell membrane penetration of conventional L-peptide activator restrict its development. To overcome these drawbacks, this study is proposed to develop in vivo stability and delivery problem of peptide activator as well as anti-tumor efficiency by D-peptides and stapled strategy combined with targeted delivery system. Peptide activators of p53 with D-style amino acid improve its stability against enzyme, thereby enhancing its biological stability; stapled peptides strategy can improve intracellular delivery of peptide, RGD modified drug delivery system will realize the tumor targeting delivery of peptide. With all these methods, it is possible to enhance antitumor activity in vivo.

英文关键词： p53 activator;stapled D-peptide;structural optimization;MDM2/MDMX;tumor targetting delivery