Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides |
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Authors: | Dr. Punit Upadhyaya Dr. Ziqing Qian Dr. Nicholas G. Selner Sarah R. Clippinger Prof. Dr. Zhengrong Wu Dr. Roger Briesewitz Prof. Dr. Dehua Pei |
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Affiliation: | 1. Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA);2. Department of Pharmacology, The Ohio State University, 5065 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210 (USA) |
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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. |
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Keywords: | cancer cell‐penetrating peptides cyclic peptides protein– protein interactions Ras signaling |
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