Identification of ras/raf binding site and design of interfering peptide with potential clinical application

Abstract

Despite intensive effort, no effective pharmacological inhibitors of the Ras oncoprotein have been reached the clinic given the impression that Ras proteins are undruggable. However, progresses have been made in several directions to manipulate Ras.In this manuscript, we describe a novel and promising approach for specifically targeting the Ras/Raf interaction. We have identified the amino acid sequence involved in the binding of Ras to Raf. The amino acids of the binding site were coupled to an optimized penetrating peptide in order to generate a chimeric peptide, Mut3DPT-Ras, able to penetrate the cells and target Ras/Raf interaction. We demonstrate that this protease-resistant peptide has an in vitro apoptotic effect on several cancer cell lines and on primary cells isolated from chronic lymphocytic leukemia (CLL) as well as an antitumoral effect on chronic lymphocytic leukemialike and lymphoma xenograft model. The new generated peptide allows the modulation of the Ras/Raf interaction and might have a potential as a new therapeutic approach for cancer treatment.