Dawber, R.S., Gimenez, D., Batchelor, M. et al. (4 more authors) (2024) Inhibition of Aurora‐A/N‐Myc protein–protein interaction using peptidomimetics: Understanding the role of peptide cyclization. ChemBioChem, 25 (2). e202300649. ISSN 1439-4227
Abstract
Using N‐Myc61‐89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N‐Myc/Aurora‐A protein–protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these – N‐Myc73‐94‐N85C/G89C‐mal, is shown to favour a more Aurora‐A compliant binding ensemble in comparison to the linear wild‐type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora‐A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora‐A surface. Taken together this work unveils the first orthosteric N‐Myc/Aurora‐A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH. 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. |
Keywords: | Aurora-A kinase; constrained peptides; N-Myc; protein-protein interactions |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Dec 2023 12:53 |
Last Modified: | 24 Jan 2024 15:56 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/cbic.202300649 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:206129 |