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5-Aminothiazoles Reveal a New Ligand-Binding Site on Prolyl Oligopeptidase Which is Important for Modulation of Its Protein-Protein Interaction-Derived Functions.
Pätsi, Henri T; Kilpeläinen, Tommi P; Jumppanen, Mikael; Uhari-Väänänen, Johanna; Wielendaele, Pieter Van; De Lorenzo, Francesca; Cui, Hengjing; Auno, Samuli; Saharinen, Janne; Seppälä, Erin; Sipari, Nina; Savinainen, Juha; De Meester, Ingrid; Lambeir, Anne-Marie; Lahtela-Kakkonen, Maija; Myöhänen, Timo T; Wallén, Erik A A.
Afiliación
  • Pätsi HT; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Kilpeläinen TP; Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Jumppanen M; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Uhari-Väänänen J; Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Wielendaele PV; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • De Lorenzo F; Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Cui H; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
  • Auno S; Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Saharinen J; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Seppälä E; School of Medicine/Biomedicine, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 8, Kuopio 70211, Finland.
  • Sipari N; Viikki Metabolomics Unit, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland.
  • Savinainen J; School of Medicine/Biomedicine, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 8, Kuopio 70211, Finland.
  • De Meester I; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • Lambeir AM; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • Lahtela-Kakkonen M; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
  • Myöhänen TT; Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
  • Wallén EAA; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
J Med Chem ; 67(7): 5421-5436, 2024 Apr 11.
Article en En | MEDLINE | ID: mdl-38546708
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Serina Endopeptidasas / Prolil Oligopeptidasas Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Serina Endopeptidasas / Prolil Oligopeptidasas Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Estados Unidos