Thioamide substitution to probe the hydroxyproline recognition of VHL ligands

Pedro Soares, Xavier Lucas, Alessio Ciulli (Lead / Corresponding author)

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Abstract

Thioamide substitution influences hydrogen bond and n→π* interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central hydroxyproline moiety, and characterize their binding by fluorescence polarization, isothermal titration calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved binding mode, the substitution pattern had a pronounced impact on the ligand affinities. Together the results underscore the role of hydrogen bond and n→π* interactions in fine-tuning hydroxyproline recognition by VHL.
Original languageEnglish
Pages (from-to)2992-2995
Number of pages4
JournalBioorganic & Medicinal Chemistry
Volume26
Issue number11
Early online date23 Mar 2018
DOIs
Publication statusPublished - 15 Jul 2018

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Keywords

  • n → π interaction
  • PROTACs
  • Protein-ligand interactions
  • Thioamides
  • VHL ligands
  • Hydroxyproline/chemistry
  • Drug Stability
  • Humans
  • Von Hippel-Lindau Tumor Suppressor Protein/chemistry
  • Crystallography, X-Ray
  • Hydrogen Bonding
  • Protein Binding
  • Ligands
  • Thioamides/chemistry

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