Cys-Cys and Cys-Lys Stapling of Unprotected Peptides Enabled by Hypervalent Iodine Reagents

Angew Chem Int Ed Engl. 2021 Apr 12;60(16):9022-9031. doi: 10.1002/anie.202014511. Epub 2021 Mar 8.

Abstract

Easy access to a wide range of structurally diverse stapled peptides is crucial for the development of inhibitors of protein-protein interactions. Herein, we report bis-functional hypervalent iodine reagents for two-component cysteine-cysteine and cysteine-lysine stapling yielding structurally diverse thioalkyne linkers. This stapling method works with unprotected natural amino acid residues and does not require pre-functionalization or metal catalysis. The products are stable to purification and isolation. Post-stapling modification can be accessed via amidation of an activated ester, or via cycloaddition onto the formed thioalkyne group. Increased helicity and binding affinity to MDM2 was obtained for a i,i+7 stapled peptide.

Keywords: bioconjugation; helicity; hypervalent iodine reagents; late-stage functionalization; peptide stapling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cysteine / chemistry*
  • Indicators and Reagents / chemistry*
  • Iodine / chemistry*
  • Lysine / chemistry*
  • Molecular Structure
  • Peptides / chemistry*

Substances

  • Indicators and Reagents
  • Peptides
  • Iodine
  • Lysine
  • Cysteine