Inhibition of Aurora-A/N-Myc protein–protein interaction using peptidomimetics: Understanding the role of peptide cyclization

19 September 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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-Myc61-89-E80C/E84C-mal – a relatively small ligand efficient peptide, 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.

Keywords

protein-protein interactions • N-Myc • Aurora-A kinase • constrained peptides

Supplementary materials

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