Toward Understanding the Molecular Recognition of Albumin by p53-Activating Stapled Peptide ATSP-7041

Abstract

Reactivation of tumor-suppressing activity of p53 protein by targeting its negative regulator MDM2/MDMX has been pursued as a potential anticancer strategy. A promising dual inhibitor of MDM2/MDMX that has been developed and is currently in clinical trials is the stapled peptide ATSP-7041. The activity of this molecule is reported to be modulated in the presence of serum. Albumin is the most abundant protein in serum and is known to bind reversibly to several molecules. To study this interaction, we develop a protocol combining molecular modeling, docking, and simulations. Exhaustive docking of the peptide with representative simulated structures of human serum albumin led to the identification of probable binding sites on the surface of the protein, including both known canonical and novel binding sites. Sequence differences at putative peptide-binding sites in human and mouse albumin result in differing interaction energies with the peptide and enable us to rationalize the observed differences in vivo. In general, the findings should help in guiding the design of features in such peptides that may affect their distribution and cell permeability, opening a new window in structure-guided design strategies.

Designing stapled peptides to inhibit protein‐protein interactions: An analysis of successes in a rapidly changing field

“…A few examples of the application of MM/GBSA to stapled peptides have been reported, which helped understand the role of hydration and flexibility in stapled‐peptide binding. [ 46,99–101 ]…”

“…who successfully modelled the flexible regions during p53 peptide binding to the MDM2 protein receptor, [ 102 ] using the CABS‐dock method which accommodates large‐scale structural rearrangements (Figure 5C); [ 103 ] and Tiwari et al . who successfully modelled docking of the p53‐activating peptide ATSP‐7041 to albumin, [ 46 ] using the protein‐protein docking program ATTRACT. [ 104 ]…”

“…A few examples of the application of MM/GBSA to stapled peptides have been reported, which helped understand the role of hydration and flexibility in stapledpeptide binding. [46,[99][100][101] Using docking algorithms to predict specific binding poses for large ligands and peptides is more challenging than for typical druglike small molecules. First, the PPI binding surface is usually larger and lacking in distinct features, with more hydrophobic contacts than binding pockets for small molecules.…”

“…who successfully modelled docking of the p53-activating peptide ATSP-7041 to albumin, [46] using the protein-protein docking program ATTRACT. [104] F I G U R E 4 Adapting biological methods to the rapid screening of stapled peptides.…”

“…But whilst we have focussed this review on these enhancements, noting the expanding interest of pharmaceutical companies for novel peptides, [41] in some cases more "classical approaches" might provide a better alternative to stapling. [42,43] Rather than highlighting solely standard PPI targets (e.g., p53-MDM2/MDMX, [44][45][46][47][48] BCL9/ β-catenin, [49] BCL-2[BAX]/BCL-X L , [50] HIV gp41/10E8 antibody, [51] LEDGF-p75/HIV-IN) [52] , we have included a broad range of examples from the very recent literature to show how widely peptide stapling is being adopted.…”