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