Thioamide substitution to probe the hydroxyproline recognition of VHL ligands.

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

SUBMITTER: Soares P 

PROVIDER: S-EPMC6008493 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature