Department of College of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Molecules. 2021 Feb 25;26(5):1225. doi: 10.3390/molecules26051225.
WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein-protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.
WD40 是一种普遍存在的结构域，存在于至少 361 个人类蛋白中，作为支架形成蛋白复合物。其中，WDR5 蛋白是几个蛋白复合物中的重要介质，在组蛋白修饰和染色质重塑中发挥作用。因此，它被认为是一种有前途的涉及抗癌药物开发的表观遗传靶点。鉴于 WDR5 的蛋白-蛋白相互作用性质，我们发起了一项发现 WDR5 新型肽模拟抑制剂的活动。在本研究中，我们利用噬菌体展示技术，用基于二硫键的环肽噬菌体文库进行筛选。进行了五轮生物淘选，分离出的克隆进行测序。通过分析序列，共合成了五个肽段进行结合实验。结果显示，四个肽段具有中等的结合亲和力。最后，通过解析 WDR5-肽共结晶结构揭示了详细的结合相互作用。
