5‑Aminothiazoles Reveal a New Ligand-Binding Site on Prolyl Oligopeptidase Which is Important for Modulation of Its Protein–Protein Interaction-Derived Functions

A series of novel 5-aminothiazole-based ligands for prolyl
oligopeptidase
(PREP) comprise selective, potent modulators of the protein–protein
interaction (PPI)-mediated functions of PREP, although they are only
weak inhibitors of the proteolytic activity of PREP. The disconnected
structure–activity relationships are significantly more pronounced
for the 5-aminothiazole-based ligands than for the earlier published
5-aminooxazole-based ligands. Furthermore, the stability of the 5-aminothiazole
scaffold allowed exploration of wider substitution patterns than that
was possible with the 5-aminooxazole scaffold. The intriguing structure–activity
relationships for the modulation of the proteolytic activity and PPI-derived
functions of PREP were elaborated by presenting a new binding site
for PPI modulating PREP ligands, which was initially discovered using
molecular modeling and later confirmed through point mutation studies.
Our results suggest that this new binding site on PREP is clearly
more important than the active site of PREP for the modulation of
its PPI-mediated functions.