多价的肽用于转录因子Fos/Jun和E47的竞争抑制及抗肿瘤活性研究

项目名称： 多价的肽用于转录因子Fos/Jun和E47的竞争抑制及抗肿瘤活性研究

项目编号： No.21202051

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机化学

项目作者： 汪萍

作者单位： 华中农业大学

项目金额： 25万元

中文摘要： 转录因子参与真核生物体内复杂体系的信号转录和调控过程，其中包括细胞增殖和凋亡等，因此日渐成为抗癌研究的新兴靶标，而抑制转录因子和DNA结合的竞争型多肽的研究引起了广泛兴趣，但这类配体却有活性不高、结合能力弱等缺点。本课题采用多价肽的结合模式，通过多价配体的协同作用将与DNA的结合能力提高了指数倍。选用与癌细胞信号激活相关的两种典型结构转录因子为靶位：Jun/Fos和E47。运用三种策略：一，通过二价肽的可逆环化，提高肽与DNA结合能力的同时，又抑制对转录很关键的双链的打开，提高抑制活性；二，通过噬菌体演示技术，修饰和筛选肽链序列，使与DNA选择性结合的能力更优；三，将肽类竞争型抑制配体对DNA的序列识别能力，与高活性却缺乏序列特异性的DNA交联剂类抗肿瘤药物相结合，设计成序列导向型高活性的多价肽类杂配体抗肿瘤药物分子。这些研究将为基因的人工调控和抗肿瘤药物发展提供新的思路和理论依据。

中文关键词： 多价肽；转录因子；序列特异性；抗肿瘤药物；

英文摘要： Transcription factors are one of the most important components of gene regulatory networks to mudulate diverse celluar and physiological activities of eukaryotic biology, including cell proliferation and apoptosis.It is becoming a increased interesting anticancer target. One of the major methods developed for inerfering with transcription has been the design of peptides to interact directly with DNA. But the strategy has not shown appropriate activities because of poor binding affinity with DNA. In this proposal, multivalent peptides are designed to bind DNA, which would exponentially increase activities by chelating effects. Two classic transcription factors related with oncogenic activation are chose, Fos/Jun(bZIP) and E47(bHLH). The three multivalent strategies are including: a) Cyclizing bivalent peptides to improve the inhibition of transcription. b) Screening more matched multivalent peptides to DNA structure and DNA sequence by phage display. c)Combining excellent activities of DNA crosslinking agents with bivalent peptides to construct novel trivalent ligands. The studies of the project would develop new strategies for anticancer design and artificial gene-regulation.

英文关键词： multivalent peptide；transcription factors；sequence specificity；antitumor drug；