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From chemRxiv
University of Birmingham, Imperial College London, University of Bristol, University of Leeds, Hertfordshire

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. 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. Thus, backbone N-Methylation may represent a useful modification within the peptidomimetic toolbox to probe β-strand mediated coupled binding and folding interactions and to develop short peptides that inhibit these less targeted PPIs.
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Published on November 16, 2023
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