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

Author

Listed:
  • Leonard Sewald

    (University Duisburg-Essen)

  • Werner W. A. Tabak

    (University Duisburg-Essen)

  • Lorenz Fehr

    (University Duisburg-Essen)

  • Samuel Zolg

    (University of Freiburg)

  • Maja Najdzion

    (University Duisburg-Essen)

  • Carlo J. A. Verhoef

    (University Duisburg-Essen
    Eindhoven University of Technology)

  • David Podlesainski

    (University Duisburg-Essen
    Ruhr University Bochum)

  • Ruth Geiss-Friedlander

    (University of Freiburg)

  • Alfred Lammens

    (Proteros Biostructures GmbH)

  • Farnusch Kaschani

    (University Duisburg-Essen)

  • Doris Hellerschmied

    (University Duisburg-Essen)

  • Robert Huber

    (University Duisburg-Essen
    Max-Planck-Institute of Biochemistry
    Technical University of Munich)

  • Markus Kaiser

    (University Duisburg-Essen)

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.

Suggested Citation

  • Leonard Sewald & Werner W. A. Tabak & Lorenz Fehr & Samuel Zolg & Maja Najdzion & Carlo J. A. Verhoef & David Podlesainski & Ruth Geiss-Friedlander & Alfred Lammens & Farnusch Kaschani & Doris Hellers, 2025. "Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58493-z
    DOI: 10.1038/s41467-025-58493-z
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    References listed on IDEAS

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    1. L. Robert Hollingsworth & Humayun Sharif & Andrew R. Griswold & Pietro Fontana & Julian Mintseris & Kevin B. Dagbay & Joao A. Paulo & Steven P. Gygi & Daniel A. Bachovchin & Hao Wu, 2021. "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation," Nature, Nature, vol. 592(7856), pages 778-783, April.
    2. Nathalie Beaufort & Linda Ingendahl & Melisa Merdanovic & Andree Schmidt & David Podlesainski & Tim Richter & Thorben Neumann & Michael Kuszner & Ingrid R. Vetter & Patricia Stege & Steven G. Burston , 2024. "Rational correction of pathogenic conformational defects in HTRA1," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
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