An orthosteric inhibitor of the Ras-Sos interaction

Disruption of protein-protein interactions can be accomplished using alpha helical mimics of one of the interacting proteins. This approach has been used to disrupt Ras-Sos interactions which are key for cellular signal transduction pathways. A hydrogen bond surrogate (HBS) approach was used to enhance helicity of the peptide and substitution of non-interacting residues with polar amino acids was used to make the peptide more soluble. In vitro and in vivo assays were performed to determine that the optimized peptidomimetic binds to the Sos binding site of Ras, but keeps GDP from being exchanged for GTP, and therefore keeps the downstream proteins from being activated.