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.
Original language | English |
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Article number | e202300649 |
Number of pages | 9 |
Journal | ChemBioChem |
Early online date | 31 Oct 2023 |
DOIs | |
Publication status | E-pub ahead of print - 31 Oct 2023 |
Bibliographical note
Acknowledgments:This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC, BB/V003577/1). RSD was supported by a studentship from the MRC Discovery Medicine North (DiMeN) Doctoral Training Partnership (MR/N013840/1). We thank Eoin Leen for useful discussions and contributions to protein production, Nasir Khan (CD), Arnout Kalverda (NMR), Mark Howard (NMR) for their support and assistance in this work. We thank Eileen Kennedy for useful discussions relating to constrained peptide design.
Keywords
- protein-protein interactions
- Aurora-A kinase
- N-Myc
- constrained peptides