An orthosteric inhibitor of the Ras-Sos interaction

• Published in: Nature chemical biology Vol. 7; no. 9; pp. 585 - 587
• Main Authors: Patgiri, Anupam, Yadav, Kamlesh K, Arora, Paramjit S, Bar-Sagi, Dafna
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 17.07.2011; Nature Publishing Group
• Subjects: 631/154/555; 631/80/86; 631/92/469; Amino Acid Sequence; Biochemical Engineering; Biochemistry; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Biomimetics; Bioorganic Chemistry; brief-communication; Cell Biology; Cell Line; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Down-Regulation; Drug Design; Genetic research; Humans; Kinases; Molecular Sequence Data; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; ras Guanine Nucleotide Exchange Factors - antagonists & inhibitors; ras Guanine Nucleotide Exchange Factors - chemistry; Reagents; Signal Transduction - drug effects; Son of Sevenless Protein, Drosophila - antagonists & inhibitors; Son of Sevenless Protein, Drosophila - chemistry
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.612

A stabilized helical peptide mimic of a key helix from the guanine nucleotide exchange factor Sos interferes with Ras-Sos interaction and inhibits Ras signaling in response to receptor tyrosine kinase activation. Mimics of α-helices on protein surfaces have emerged as powerful reagents for antagonizing protein-protein interactions, which are difficult to target with small molecules. Here we describe the design of a cell-permeable synthetic α-helix, based on the guanine nucleotide exchange factor Sos, that interferes with Ras-Sos interaction and downregulates Ras signaling in response to receptor tyrosine kinase activation.