Abstract
AbstractEasy 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.
Highlights
Protein-protein interactions (PPI) mediate a wide array of signaling pathways in the cell
The helical conformation of short peptides is less stable than when the sequences are part of proteins, and they are rapidly degraded by proteases
We have reported the synthesis of new bifunctional hypervalent iodine reagents and their use for peptide stapling
Summary
Protein-protein interactions (PPI) mediate a wide array of signaling pathways in the cell Many of such interactions involve binding through a-helical sequences. Stapling—covalently linking two amino acids residues of peptides on the same face of an a-helix—has been shown to enforce the helical conformation and improve the stability of peptides. It enhances their cell membrane permeability and their potential to be used as drugs.[3] When developing a bioactive stapled peptide, the structure, length, lipophilicity and reactivity of the introduced linker is important.[4,5] The linkers can be used to improve the solubility
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