组蛋白的赖氨酸乙酰化的“阅读器”—溴结构域蛋白(Bromodomain)，是表观遗传学中重要的分子机制之一，调控基因的表达与功能，与多种疾病发生、发展密切相关。在溴结构域蛋白家族中, BRD4已经被作为一种重要的药物靶标，其抑制剂可被发展用来治疗各种疾病 (包括癌症和炎症等)。现有的BRD4小分子抑制剂共同的弱点是不能很好区分BRD4和它的同源蛋白，选择性较差，以及抑制剂的抗癌活性有待改进。为了获得更佳选择性和活性的BRD4 抑制剂，基于多肽展现的选择性优势和申请人的前期工作基础，本项目拟开展: (1)运用高通量筛选方法 (OBOC 和微阵列), 筛选出高选择性和高亲和力结合BRD4的多肽抑制剂和优化选择性多肽的氨基酸序列; (2)进一步探索先导多肽抑制剂的抗癌活性 (如肺癌和乳腺癌等); (3)基于这些选择性多肽设计合成相应的生物探针应用于BRD4蛋白捕获和灵敏检测。

Bromodomain, as the “reader” of the lysine acetylation in histone proteins and also as one of the most important molecular mechanisms in epigenetics, are linked to the regulation of gene expression and function and are also relevant to the progress of many diseases. Among Bromodomain families, BRD4 has been proved to be one of potential and very important drug targets for drug research and developments. BRD4 inhibitors can be used to treat different kinds of diseases including cancer and inflammation. However, the obvious and common limitations for current small molecule based non-peptide inhibitors include lack of selectivity and inhibition activity, which can be further improved. To answer these scientific questions, based on the natural advantages of peptide in terms of binding selectivity and also our previous relevant studies in this research area, we will perform the studies as below: (1) By using the high-throughput screening technologies (One-Bead-One-Compound (OBOC) and microarray), identify peptide inhibitors against BRD4 with good selectivity and high binding against BRD4 and obtain the improved and selective peptide amino acid sequences; (2) Further explore and investigate the anti-cancer activities (such as Lung cancer and breast cancer etc.) with good lead peptide inhibitors candidates; (3) Design , synthesize and apply these selective peptide-derived environmental responsive bioprobes for protein capturing and detection agents for BRD4.