靶向蛋白相互作用是当前新药研发和化学生物学的重要研究领域。本项目以大环化的蛋白二级结构为优势骨架，通过药物研发中的新兴技术——DNA编码分子库技术，针对蛋白相互作用，合成专用分子库。项目拟构建三个基于恒定大环骨架的DNA编码蛋白表位模拟物库，对与重大疾病相关的蛋白相互作用靶标：HER2/neu和肿瘤坏死因子（TNF-a）进行筛选，得到与抗体具有类似高特异性、高亲和力的合成配体。项目将解决传统药物研发中蛋白相互作用“难成药”的困难，针对不同类型蛋白相互作用，探索获得靶向合成配体的通用技术途径。进一步地，本研究还将在筛选DNA编码蛋白表位模拟物库的基础上，发展筛选获得的合成配体的功能化应用，例如小分子偶联药物和蛋白靶向分子探针。

Targeting Protein-Protein Interactions (PPIs) is a wide-open field for drug discovery and chemical biology. In this study, we plan to address the issue with a dedicated compound library design featuring macrocyclic protein secondary structures as privileged scaffolds, by employing DNA-Encoded Chemical Library Technology, an emerging drug discovery technology. Three DNA-encoded protein epitope mimetic libraries will be constructed based on different types of constant macrocyclic scaffolds. Further selection campaigns against important pharmaceutical PPI targets like HER2/neu and TNF-a will result in synthetic binders with antibody-like high specificity and affinity. These results would illustrate a general strategy to generate synthetic binders against “difficult targets” like PPIs. Furthermore, binders harvested from the DNA-encoded protein epitope mimetic libraries could enable practical applications, such as small-molecule drug conjugates and protein-specific chemical probes.