Raman active diyne-girder conformationally constrained p53 stapled peptides bind to MDM2 for visualisation without fluorophores.

ABSTRACT: Peptide stapling is an effective strategy to stabilise α-helical peptides, enhancing their bioactive conformation and improving physiochemical properties. In this study, we apply our novel diyne-girder stapling approach to the MDM2/MDMX α-helical binding region of the p53 transactivation domain. By incorporation of an unnatural amino acid to create an optimal i, i + 7 bridge length, we developed a highly α-helical stapled peptide, 4, confirmed via circular dichroism. This diyne-girder-stapled peptide demonstrated enhanced helicity and nanomolar binding affinity for MDM2, as assessed by fluorescence polarisation. Crucially, peptide 4 exhibited strong selectivity for MDM2, with approximately 100-fold reduced affinity for MDMX. Molecular modeling and docking studies sugge

SUBMITTER: Morgan DC 

PROVIDER: S-EPMC11741006 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature