Structure of the Stapled p53 Peptide Bound to Mdm2

Abstract

Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 Å resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface.

Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin

“…On the other hand, recent successes in inhibiting even extended PPIs using the hydrocarbonstapled α-helix technology (20)(21)(22)(23)(24)(25)(26)(27) suggested the possibility of using this approach toward β-catenin/TCF antagonism; this notion was strengthened by the presence of the requisite α-helical interaction domain in TCF. Helix stapling entails the introduction of a synthetic all-hydrocarbon brace across one face of an α-helical peptide, which in numerous cases has been shown to stabilize the bioactive α-helical conformation, to increase binding affinity for the target, to decrease the rate of proteolytic degradation, and most importantly, to effect robust cell penetration by endocytic vesicle trafficking (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Importantly, stapled peptides have demonstrated robust efficacy in animal models of human disease, including T-cell acute lymphoblastic leukemia, by direct targeting of the Notch transactivation complex (24) and BCL2-driven lymphoma (27).…”

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion

“…A possible explanation could be the formation of potency-enhancing hydrophobic interactions between the hydrophobic staple of 11 and the VPAC 2 receptor, as previously observed in the case of a stapled p53 peptide bound to Mdm2. 34 Generally, the alpha helical content of peptide hormones, e.g., glucagon, correlates well with their functional potency; however, comparison of CD spectra recorded for peptides 1−14 failed to provide a clear trend between helicity and potency. On the basis of these results, the most potent cyclic peptides, 5 and 11, were evaluated for their ability to increase glucosestimulated insulin secretion (GSIS) in pancreatic rat islets.…”

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

“…To address the need for a more in-depth understanding on how peptide stapling stabilizes peptide helices, all-atom Monte Carlo folding simulations were performed [53]. These insights are currently explored as tools in chemical biology or to improve the drug-like properties of therapeutically relevant stapled peptides [54][55][56][57][58][59][60]. A recent overview of hydrocarbon-stapled peptides, which highlights their use as biomedical research tool and prototype therapeutics, is recommended to the reader who is interested in more biological applications [61].…”