Protein-protein interactions (PPIs) play a crucial mechanistic role in regulating health and disease biology. PPIs thus represent important targets in drug discovery. Competitive/orthosteric PPI inhibition has been historically challenging given that proteinprotein interfaces are relatively large and lack the well-defined pockets that are characteristic of traditional drug targets. Although success has been achieved using fragment-based approaches, small-molecules developed from screening libraries and computational methods, there remains a need to develop new enabling methods and modalities for PPI modulation. Peptides are attractive given they offer functionally optimal molecular recognition properties. Significant efforts have been invested in developing peptidomimetic inhibitors of α-helix mediated PPIs, with cyclization employed as a tool to bias a given peptide toward its bioactive conformation, suppress proteolysis, and improve cell uptake. Emerging studies extend this approach to β-strand and loop 13 mediated PPIs, whilst screening tools have yielded cyclic and bicyclic peptides for a range of other targets. However, strategies for the design of constrained peptides that mimic noncanonical secondary structures are less well developed. Herein, we used rational design to develop a peptidomimetic inhibitor of the TACC3/Aurora-A interaction. Judicious incorporation of non-natural amino acids and constraints led to a peptide with enhanced affinity for its target as a consequence of excluding accessible conformations thus raising the ground state energy of the conformational ensemble. The power of these peptidomimetic tools to understand the target protein is illustrated through experiments showing that they activate Aurora-A kinase and inhibit a further PPI (N-Myc/Aurora-A) at a remote site.