title: Linear aliphatic dialkynes as alternative linkers for double-click stapling of p53-derived peptides.
abstract: We investigated linear aliphatic dialkynes as a new structural class of i,i+7 linkers for the double-click stapling of p53-based peptides. The optimal combination of azido amino acids and dialkynyl linker length for MDM2 binding was determined. In a direct comparison between aliphatic and aromatic staple scaffolds, the aliphatic staples resulted in superior binding to MDM2 in vitro and superior p53-activating capability in cells when using a diazidopeptide derived from phage display. This work demonstrates that the nature of the staple scaffold is an important factor that can affect peptide bioactivity in cells.
authors.affiliation: University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK).
authors.forename: Yu Heng
authors.initials: YH
authors.lastname: Lau
authors.forename: Peterson
authors.initials: P
authors.lastname: de Andrade
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: McKenzie
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D000480:Alkynes / Q000737:chemistry* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D057930:Click Chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D001386:Azides; D010455:Peptides; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: anticancer agents; click chemistry; macrocycles; peptides; stapling