Fletcher, JM, Horner, KA, Bartlett, GJ et al. (3 more authors) (2018) De novo coiled-coil peptides as scaffolds for disrupting protein–protein interactions. Chemical Science, 9 (39). pp. 7656-7665. ISSN 2041-6520
Abstract
Protein–protein interactions (PPIs) play pivotal roles in the majority of biological processes. Therefore, improved approaches to target and disrupt PPIs would provide tools for chemical biology and leads for therapeutic development. PPIs with α-helical components are appealing targets given that the secondary structure is well understood and can be mimicked or stabilised to render small-molecule and constrained-peptide-based inhibitors. Here we present a strategy to target α-helix-mediated PPIs that exploits de novo coiled-coil assemblies and test this using the MCL-1/NOXA-B PPI. First, computational alanine scanning is used to identify key α-helical residues from NOXA-B that contribute to the interface. Next, these residues are grafted onto the exposed surfaces of de novo designed homodimeric or heterodimeric coiled-coil peptides. The resulting synthetic peptides selectively inhibit a cognate MCL-1/BID complex in the mid-nM range. Furthermore, the heterodimeric system affords control as inhibition occurs only when both the grafted peptide and its designed partner are present. This establishes proof of concept for exploiting peptides stabilised in de novo coiled coils as inhibitors of PPIs. This dependence on supramolecular assembly introduces new possibilities for regulation and control.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Editors: |
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Copyright, Publisher and Additional Information: | This article is licensed under a Creative Commons CC Attribution 3.0 Unported License https://creativecommons.org/licenses/by/3.0/ |
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) |
Depositing User: | Symplectic Publications |
Date Deposited: | 28 Sep 2018 14:04 |
Last Modified: | 14 Dec 2018 11:19 |
Status: | Published |
Publisher: | Royal Society of Chemistry |
Identification Number: | 10.1039/C8SC02643B |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:136054 |