Stapled Peptides as HIF-1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

Kristina Hetherington, Zsofia Hegedus, Thomas A Edwards, Richard B Sessions, Adam Nelson, Andrew J Wilson

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Protein-protein interactions (PPIs) control virtually all cellular processes and have thus emerged as potential targets for development of molecular therapeutics. Peptide-based inhibitors of PPIs are attractive given that they offer recognition potency and selectivity features that are ideal for function, yet, they do not predominantly populate the bioactive conformation, frequently suffer from poor cellular uptake and are easily degraded, for example, by proteases. The constraint of peptides in a bioactive conformation has emerged as a promising strategy to mitigate against these liabilities. In this work, using peptides derived from hypoxia-inducible factor 1 (HIF-1α) together with dibromomaleimide stapling, we identify constrained peptide inhibitors of the HIF-1α/p300 interaction that are more potent than their unconstrained sequences. Contrary to expectation, the increased potency does not correlate with an increased population of an α-helical conformation in the unbound state as demonstrated by experimental circular dichroism analysis. Rather, the ability of the peptide to adopt a bioactive α-helical conformation in the p300 bound state is better supported in the constrained variant as demonstrated by molecular dynamics simulations and circular dichroism difference spectra.

Original languageEnglish
Pages (from-to)7638-7646
Number of pages9
JournalChemistry - A European Journal
Volume26
Issue number34
DOIs
Publication statusPublished - 18 Jun 2020

Keywords

  • Circular Dichroism
  • E1A-Associated p300 Protein/antagonists & inhibitors
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
  • Peptides/chemistry
  • Protein Conformation, alpha-Helical

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