Protein-protein interactions (PPIs) are often mediated by α-helices. Thus, short α-helical peptides have a potential to act as inhibitors of PPIs, making them a desirable target. Peptide stapling - covalent linkage of two amino acid side chains, can improve the stability, cell-permeability and binding affinity of short α-helices. Therefore, an easy access to a wide range of structurally varied stapled peptides is crucial for the development of efficient inhibitors of PPIs.<br/>Selective cysteine alkynylation using hypervalent iodine reagents has been previously developed in our group. This method has now been extended to two-component cysteine-cysteine and cysteine-lysine stapling. Herein, we will present successful application of novel bis-functional hypervalent iodine reagents that yield structurally diverse thioalkyne linkers. The method utilizes unprotected peptides and enables post-stapling modifications via amidation of an activated ester, or via cycloaddition onto the formed thioalkyne group. Stapling of a peptide derived from p53 protein showed significant increase in helicity and binding affinity to MDM2.

Cys-Cys and Cys-Lys stapling of unprotected peptides enabled by hypervalent iodine reagents

ACS Spring Meeting 2021

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