Upadhyaya Punit, Qian Ziqing, Selner Nicholas G, Clippinger Sarah R, Wu Zhengrong, Briesewitz Roger, Pei Dehua
Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
Department of Pharmacology, The Ohio State University, 5065 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210 (USA).
Angew Chem Int Ed Engl. 2015 Jun 22;54(26):7602-6. doi: 10.1002/anie.201502763. Epub 2015 May 7.
Ras genes are frequently activated in human cancers, but the mutant Ras proteins remain largely "undruggable" through the conventional small-molecule approach owing to the absence of any obvious binding pockets on their surfaces. By screening a combinatorial peptide library, followed by structure-activity relationship (SAR) analysis, we discovered a family of cyclic peptides possessing both Ras-binding and cell-penetrating properties. These cell-permeable cyclic peptides inhibit Ras signaling by binding to Ras-GTP and blocking its interaction with downstream proteins and they induce apoptosis of cancer cells. Our results demonstrate the feasibility of developing cyclic peptides for the inhibition of intracellular protein-protein interactions and of direct Ras inhibitors as a novel class of anticancer agents.
Ras基因在人类癌症中经常被激活，但由于突变的Ras蛋白表面缺乏明显的结合口袋，通过传统的小分子方法仍基本“难以成药”。通过筛选组合肽库，随后进行构效关系（SAR）分析，我们发现了一类兼具Ras结合和细胞穿透特性的环肽。这些可穿透细胞的环肽通过与Ras-GTP结合并阻断其与下游蛋白的相互作用来抑制Ras信号传导，并诱导癌细胞凋亡。我们的结果证明了开发环肽以抑制细胞内蛋白质-蛋白质相互作用以及开发直接Ras抑制剂作为一类新型抗癌药物的可行性。
