title: Inhibition of Ras signaling by blocking Ras-effector interactions with cyclic peptides.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
authors.forename: Punit
authors.initials: P
authors.lastname: Upadhyaya
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Selner
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Clippinger
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, The Ohio State University, 5065 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210 (USA). Roger.Briesewitz@osumc.edu.
authors.forename: Roger
authors.initials: R
authors.lastname: Briesewitz
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA). pei.3@osu.edu.
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D006801:Humans; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D010456:Peptides, Cyclic; D018631:ras Proteins
keywords: Ras signaling; cancer; cell-penetrating peptides; cyclic peptides; protein-protein interactions