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

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

Abstract

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.

Keywords

protein-protein interactions • peptidomimetics • β-strand-mediated interactions • intrinsically disordered regions • binding-mechanisms

Supplementary materials

Title
Description
Actions
Title
Supporting Information
Description
experimental methods, additional data figures and characterization
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.