2. Academic Validation
  3. 5-Aminothiazoles Reveal a New Ligand-Binding Site on Prolyl Oligopeptidase Which is Important for Modulation of Its Protein-Protein Interaction-Derived Functions

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

  • J Med Chem. 2024 Apr 11;67(7):5421-5436. doi: 10.1021/acs.jmedchem.3c01993.
Henri T Pätsi 1,  Tommi P Kilpeläinen 2,  Mikael Jumppanen 1,  Johanna Uhari-Väänänen 2,  Pieter Van Wielendaele 3,  Francesca De Lorenzo 2,  Hengjing Cui 4,  Samuli Auno 2,  Janne Saharinen 1,  Erin Seppälä 5,  Nina Sipari 6,  Juha Savinainen 5,  Ingrid De Meester 3,  Anne-Marie Lambeir 3,  Maija Lahtela-Kakkonen 4,  Timo T Myöhänen 2 4 7,  Erik A A Wallén 1
Affiliations

Affiliations

  • 1 Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • 2 Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • 3 Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • 4 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
  • 5 School of Medicine/Biomedicine, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 8, Kuopio 70211, Finland.
  • 6 Viikki Metabolomics Unit, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland.
  • 7 Division of Pharmacology, Faculty of Medicine, University of Helsinki, P.O.Box 63, 00014 Helsinki, Finland.
PMID: 38546708 DOI: 10.1021/acs.jmedchem.3c01993
Abstract

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.

Figures
Products