title: A New Methodology for Incorporating Chiral Linkers into Stapled Peptides.
abstract: Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents for modulating protein-protein interactions. Here, we report the first two-component i,i+7 stapling methodology that makes use of two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral centre into a p53-derived stapled peptide. Post-stapling modifications to the chain were performed on-resin and enabled rapid access to various peptide derivatives from a single staple. The stapled peptides have increased helicity, protease stability and in vitro binding affinities to MDM2 compared to the equivalent unstapled peptide. This approach can be used to generate a library of diverse stapled peptides with different properties starting from a single stapled peptide, with scope for much greater functional diversity than that provided by existing stapling methodologies.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Juan C
authors.identifier: 0000-0002-3671-3809
authors.initials: JC
authors.lastname: Serrano
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: James
authors.identifier: 0000-0002-6838-8043
authors.initials: J
authors.lastname: Sipthorp
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
authors.forename: Wenshu
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
authors.forename: Laura S
authors.identifier: 0000-0001-6504-2576
authors.initials: LS
authors.lastname: Itzhaki
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Steven V
authors.identifier: 0000-0002-7816-0042
authors.initials: SV
authors.lastname: Ley
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D001559:Benzhydryl Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: C030545:4-methylbenzhydrylamine resin; D001559:Benzhydryl Compounds; D003432:Cross-Linking Reagents; D019151:Peptide Library; D010455:Peptides; D016159:Tumor Suppressor Protein p53; C506098:azidohomoalanine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000409:Alanine
keywords: chiral linkers; protein-protein interactions; solid-phase synthesis; stapled peptides; two-component stapling