Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >10¹² in vitro-translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.

中文翻译：

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发现、X 射线结构和 CPP 结合使 p53/MDM2 大环肽抑制剂的吸收成为可能

小鼠双分 2 同源物 ( MDM2 , Hdm2) 是肿瘤抑制因子 p53的重要负调节因子。使用基于 mRNA 的展示技术来筛选 >10 ¹² 体外翻译的环肽文库，我们已经鉴定了在MDM2上显示出皮摩尔效力的大环配体。X 射线晶体学揭示了一种新的结合模式，利用独特的药效团占据MDM2上的 Phe/Trp/Leu 口袋。环状细胞穿透肽 (cCPP) 与最初非细胞渗透性配体的缀合使SJSA-1 中的细胞摄取和药效学反应成为可能细胞。通过展示技术鉴定的环肽在细胞内的可用性增强，这证明了细胞内工具在药物发现项目中的应用过程。