Hetherington, K, Hegedus, Z, Edwards, TA orcid.org/0000-0002-1467-3674 et al. (3 more authors) (2020) Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency. Chemistry: A European Journal, 26 (34). pp. 7638-7646. ISSN 0947-6539
Abstract
Protein–protein interactions (PPIs) control virtually all cellular processes and have thus emerged as potential targets for development of molecular therapeutics. Peptide‐based inhibitors of PPIs are attractive given that they offer recognition potency and selectivity features that are ideal for function, yet, they do not predominantly populate the bioactive conformation, frequently suffer from poor cellular uptake and are easily degraded, for example, by proteases. The constraint of peptides in a bioactive conformation has emerged as a promising strategy to mitigate against these liabilities. In this work, using peptides derived from hypoxia‐inducible factor 1 (HIF‐1α) together with dibromomaleimide stapling, we identify constrained peptide inhibitors of the HIF‐1α/p300 interaction that are more potent than their unconstrained sequences. Contrary to expectation, the increased potency does not correlate with an increased population of an α‐helical conformation in the unbound state as demonstrated by experimental circular dichroism analysis. Rather, the ability of the peptide to adopt a bioactive α‐helical conformation in the p300 bound state is better supported in the constrained variant as demonstrated by molecular dynamics simulations and circular dichroism difference spectra.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | chemical biology; oncology; peptidomimetics; protein–protein interactions; stapled peptides |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Crystallography (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Apr 2020 12:04 |
Last Modified: | 25 Jun 2023 22:13 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/chem.202000417 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:159501 |