Peptidomimetic inhibitors of β-strand mediated protein-protein interactions: tuning binding affinity of intrinsically disordered sequences by covalent backbone modification

A significant challenge for chemical biology is to develop methods that enable targeting of protein-protein interactions (PPIs). Given that many PPIs involve a folded protein domain and a peptide that is intrinsically disordered in isolation, peptides present potential starting points for designing PPI modulators. While multiple approaches to pre-organize α-helical motifs for enhancing affinity and other properties are available, β-strand-mediated interactions are much less explored. Using the interaction between small ubiquitin-like modifiers (SUMO) and SUMO-interacting motifs (SIMs), here we show that N-methylation of the peptide backbone can effectively restrict accessible peptide conformations, predisposing them for protein recognition. Backbone N-methylation in appropriate locations results in faster target binding, and thus higher affinity, as shown by fluorescence anisotropy, relaxation-based NMR experiments, and computational analysis. We show that such higher affinities occur as a consequence of an increase in the energy of the unbound state, and a reduction in the entropic contribution to the binding and activation energies. This offers a new paradigm for developing peptide-based PPI modulators.