Stapled Peptides Inhibit Protein–Protein Interactions

  • Author: Chemistry – A European Journal
  • Published Date: 04 July 2020
  • Source / Publisher: Chemistry – A European Journal/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA
thumbnail image: Stapled Peptides Inhibit Protein–Protein Interactions

Related Societies

Interactions between two or more proteins—protein-protein interactions (PPIs)—regulate virtually all cellular processes. PPIs are important in disease development and progression, and thus, can be promising drug targets. So-called peptide "stapling" can be used as a method for targeting α-helix mediated PPIs, i.e., those in which binding is based on the docking of an α-helix from one protein into a cleft on another. In such a "stapling" approach, a peptide is constrained in an α-helical (or similar) conformation to enhance its target-binding affinity.

Andrew J. Wilson, University of Leeds, UK, and colleagues have "stapled" peptides derived from hypoxia‐inducible factor 1 (HIF‐1α) into a constrained configuration. Their aim was to target the interaction between HIF-1α and the protein p300, which involves an α-helix. The HIF-1α/p300 interaction plays a key role in tumor metabolism and is a promising anticancer target. The team used a reversible dibromomaleimide stapling to connect cysteine residues on HIF-1α peptides to pre-organize them and support the formation of an α-helix.

This "stapling" led to increased binding affinity of the peptide to p300 (simulated complex pictured) compared with the unconstrained version. This observed increase is not directly caused by an increased population of an α‐helical conformation in the unbound state. Rather, it is due to an improved  ability of the peptide to adopt a bioactive α‐helical conformation in the bound state, which is supported by the constrained configuration. According to the researchers, these results could help to improve the design of peptides that target therapeutically important proteins.



Article Views: 718

Sign in Area

Please sign in below

Additional Sign In options

Please note that to comment on an article you must be registered and logged in.
Registration is for free, you may already be registered to receive, e.g., the newsletter. When you register on this website, please ensure you view our terms and conditions. All comments are subject to moderation.

Article Comments - To add a comment please sign in

Bookmark and Share

If you would like to reuse any content, in print or online, from, please contact us first for permission. more

CONNECT: on Facebook on Twitter on YouTube on LinkedIn Sign up for our free newsletter

Magazine of Chemistry Europe (16 European Chemical Societies)published by Wiley-VCH