Grafted coiled-coil peptides as multivalent scaffolds for protein recognition

Acevedo-Jake, Amanda M., Mylemans, Bram, Kay, Danielle F., Zhang, Peiyu, Korona, Boguslawa, Rhys, Guto G. ORCID: https://orcid.org/0000-0002-0247-9495, Leney, Aneika C., Huang, Danny T., Edwards, Thomas A., Itzhaki, Laura, Woolfson, Derek N. and Wilson, Andrew J. 2025. Grafted coiled-coil peptides as multivalent scaffolds for protein recognition. ACS Chemical Biology 20 (6) , pp. 1309-1318. 10.1021/acschembio.5c00137

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Abstract

Self-assembled peptides are promising templates for the design of inhibitors of protein–protein interactions (PPIs) because they can be endowed with affinity- and selectivity-defining amino acids alongside favorable physicochemical properties such as solubility and stability. Here, we describe a tunable coiled-coil scaffold and its interaction with MCL-1, an α-helix-binding antiapoptotic protein and important target in oncology. We explore the role of oligomerization, multivalency, and cooperativity in PPI inhibition. Hot-spot residues from an MCL-1 binding peptide (NOXA-B) are grafted onto the outer surfaces of homo- and heterodimeric coiled-coil peptides to obtain inhibitors with mid-nM potency and selectivity over BCL-xL. Binding of homodimeric coiled coils to MCL-1 is positively cooperative, resulting in stabilization of both partners. Homodimeric coiled coils support the binding of two copies of the target protein. Modification of the coiled-coil sequence to favor assembly of higher-order scaffolds (trimer and tetramer) negatively impacts inhibitory potency, with AlphaFold2 modeling and biophysical data indicating a complex interplay between coiled-coil oligomerization and target binding. Together, these data establish dimeric coiled coils as the most promising of such scaffolds to develop inhibitors of α-helix-mediated PPIs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Chemistry
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Start Date: 2025-06-05
Publisher:	American Chemical Society
ISSN:	1554-8929
Date of First Compliant Deposit:	19 June 2025
Date of Acceptance:	21 May 2025
Last Modified:	10 Jul 2025 13:07
URI:	https://orca.cardiff.ac.uk/id/eprint/179201

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