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Published on: August 1, 2018
Linear aliphatic dialkynes as alternative linkers for double-click stapling of p53-derived peptides
Yu Heng Lau1, Peterson de Andrade, Grahame J McKenzie
1University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK).
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.
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