A peptide inhibitor that interferes with the activation of and signaling with Ras protein, a central component of many growth-promoting pathways in cells that can be hyperactivated in cancer or other diseases, is reported this week in Nature Chemical Biology. Strategies to inactivate or inhibit Ras-dependent signaling have proved elusive but would be beneficial for the treatment of many disorders.
The activity of Ras depends on protein-protein interactions with Sos, which converts Ras from an inactive to an active state. Sos is known to interact with Ras via a structural motif called an alpha helix. Synthetic mimics of the alpha helices on protein surfaces have emerged as a strategy for antagonizing protein-protein interactions.
Paramjit Arora, Dafna Bar-Sagi and colleagues engineered a peptide inhibitor, based on the Sos alpha helix, that interfered with Ras activation by Sos and blocked Ras-dependent signaling in cells. This study lends support to the notion that helical mimics are a viable approach for targeting protein-protein interaction interfaces and could provide the foundation for the development of Ras inhibitors for treatment of a variety of diseases.