2. Academic Validation
  3. Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors

Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors

  • Nat Commun. 2025 Apr 3;16(1):3208. doi: 10.1038/s41467-025-58493-z.
Leonard Sewald # 1,  Werner W A Tabak # 1,  Lorenz Fehr # 1,  Samuel Zolg 2,  Maja Najdzion 1,  Carlo J A Verhoef 1 3,  David Podlesainski 1 4,  Ruth Geiss-Friedlander 2,  Alfred Lammens 5,  Farnusch Kaschani 1,  Doris Hellerschmied 6,  Robert Huber 7 8 9,  Markus Kaiser 10
Affiliations

Affiliations

  • 1 Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
  • 2 Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 3 Laboratory of Chemical Biology, Department of Biomedical Engineering, Institute for Complex Molecular Systems, Eindhoven University of Technology, MB, Eindhoven, The Netherlands.
  • 4 Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.
  • 5 Proteros Biostructures GmbH, Martinsried, Germany.
  • 6 Mechanistic Cell Biology, Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
  • 7 Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
  • 8 Max-Planck-Institute of Biochemistry, Martinsried, Germany.
  • 9 TUM Senior Excellence Faculty, Technical University of Munich, Munich, Germany.
  • 10 Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany. markus.kaiser@uni-due.de.
  • # Contributed equally.
PMID: 40180908 DOI: 10.1038/s41467-025-58493-z
Abstract

Covalent chemical probes and drugs combine unique pharmacologic properties with the availability of straightforward compound profiling technologies via chemoproteomic platforms. These advantages have fostered the development of suitable electrophilic "warheads" for systematic covalent chemical probe discovery. Despite undisputable advances in the last years, the targeted development of proteome-wide selective covalent probes remains a challenge for Dipeptidyl Peptidase (DPP) 8 and 9 (DPP8/9), intracellular serine hydrolases of the pharmacologically relevant Dipeptidyl Peptidase 4 activity/structure homologues (DASH) family. Here, we show the exploration of the natural product Sulphostin, a DPP4 inhibitor, as a starting point for DPP8/9 inhibitor development. The generation of Sulphostin-inspired N-phosphonopiperidones leads to derivatives with improved DPP8/9 inhibitory potency, an enhanced proteome-wide selectivity and confirmed DPP8/9 engagement in cells, thereby representing that structural fine-tuning of the warhead's leaving group may represent a straightforward strategy for achieving target selectivity in exoproteases such as DPPs.

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