Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

De novocoiled-coil peptides as scaffolds for disrupting protein–protein interactions

Fletcher, Jordan M., Horner, Katherine A., Bartlett, Gail J., Rhys, Guto G., Wilson, Andrew J. and Woolfson, Derek N. 2018. De novocoiled-coil peptides as scaffolds for disrupting protein–protein interactions. Chemical Science 9 (39) , pp. 7656-7665. 10.1039/C8SC02643B

[thumbnail of Chem.Sci-c8sc02643b.pdf] PDF - Published Version
Available under License Creative Commons Attribution.

Download (2MB)

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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Chemistry
Additional Information: This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Publisher: Royal Society of Chemistry
ISSN: 2041-6520
Date of First Compliant Deposit: 3 November 2022
Date of Acceptance: 6 August 2018
Last Modified: 08 May 2023 09:16
URI: https://orca.cardiff.ac.uk/id/eprint/153747

Citation Data

Cited 34 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics