Introducing 3-Fluoro-4-hydroxyprolines: Synthesis, conformational analysis and stereoselective recognition by VHL E3 ligase for protein degradation.

  • ToC graphics
  • Chart 1. Chemical Structures of Hydroxyl- and Fluoro-prolines
  • Figure 1. von Hippel-Lindau E3 ligase recognition of Hyp for VHL ligands and PROTACs
  • Scheme 1. Synthesis of F-Hyps N-Protected Amino Acids
  • Figure 2. Structural assignment of F-Hyps
  • Chart 2. Chemical Structure of F-Hyps 12a–d and the Corresponding Reference Compounds
  • Figure 3. Topological and conformational analysis and H-bond donating capacity of F-Hyps.
  • Chart 3. Structures of Model HIF-1α Peptides Biophysically Evaluated in This Work
  • Figure 4. Binding affinity and binding mode of F-Hyp-containing HIF-1α peptides.
  • Figure 5. Binding affinity and binding mode of F-Hyp-containing VHL ligands
  • Figure 6. Structural basis of diasteroselective recognition of F-Hyps by VHL.
  • Figure 7. BET protein degradation induced by F-Hyp-containing PROTACs.
  • @EndriuT developed diverse synthetic routes to achieve all four diastereoisomers of unprecedented unnatural fluorinated analogues of 4-hydroxyproline (Hyp) - the most common posttranslationally modified aminoacid
  • with @_xavierlucas_ et al demonstrate using small-mol NMR, crystallography and modelling how fluorination affects the conformational preferences and H-bond capacity of the Hyp core: fluorination in F-Hyps inverts the natural preference from the C4-exo to the C4-endo pucker
  • using ITC they show that the VHL E3 ligase, which naturally recognizes C4-exo Hyp, still binds to F-Hyp-containing HIF peptides and VHL ligands - in a stereoselective fashion, which they rationalised by means of co-crystal structures and electrostatic potential calculations
  • a #PROTAC degrader containing the weak-affinity epimer of F-Hyp induced highly selective degradation of the target protein (Brd4) at concentrations much lower than the binary Kd for VHL
  • An important first step to expand the chemical space of VHL-based degrader molecules, with potential to fine-tune their PK properties and specificity too

Very proud of Lab’s work just out in @JACS by Andrea, Xavi and coworkers! well done everyone at @UoDLifeSciences and beyond, and thanks to @ERC_Research @MSCActions for funding

Read our article Open Access here.