Thioamide substitution to probe the hydroxyproline recognition of VHL ligands

Publication date: Available online 23 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Pedro Soares, Xavier Lucas, Alessio Ciulli
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.

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