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Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins

Author

Listed:
  • Umer Bin Abdul Aziz

    (Freie Universität Berlin)

  • Ali Saoud

    (Freie Universität Berlin)

  • Marcel Bermudez

    (Freie Universität Berlin
    University of Münster)

  • Maren Mieth

    (Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Amira Atef

    (Freie Universität Berlin
    Assuit University)

  • Thomas Rudolf

    (Freie Universität Berlin)

  • Christoph Arkona

    (Freie Universität Berlin)

  • Timo Trenkner

    (Leibniz Institute of Virology)

  • Christoph Böttcher

    (Freie Universität Berlin)

  • Kai Ludwig

    (Freie Universität Berlin)

  • Angelique Hoelzemer

    (Leibniz Institute of Virology
    University Medical Center Hamburg-Eppendorf (UKE))

  • Andreas C. Hocke

    (Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Gerhard Wolber

    (Freie Universität Berlin)

  • Jörg Rademann

    (Freie Universität Berlin)

Abstract

Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) from Streptococcus pneumoniae, the main cause for bacterial pneumonia. Liberation of PLY during infection leads to compromised immune system and cytolytic cell death. Here, we report discovery, development, and validation of targeted small molecule inhibitors of PLY (pore-blockers, PB). PB-1 is a virtual screening hit inhibiting PLY-mediated hemolysis. Structural optimization provides PB-2 with improved efficacy. Cryo-electron tomography reveals that PB-2 blocks PLY-binding to cholesterol-containing membranes and subsequent pore formation. Scaffold-hopping delivers PB-3 with superior chemical stability and solubility. PB-3, formed in a protein-templated reaction, binds to Cys428 adjacent to the cholesterol recognition domain of PLY with a KD of 256 nM and a residence time of 2000 s. It acts as anti-virulence factor preventing human lung epithelial cells from PLY-mediated cytolysis and cell death during infection with Streptococcus pneumoniae and is active against the homologous Cys-containing CDC perfringolysin (PFO) as well.

Suggested Citation

  • Umer Bin Abdul Aziz & Ali Saoud & Marcel Bermudez & Maren Mieth & Amira Atef & Thomas Rudolf & Christoph Arkona & Timo Trenkner & Christoph Böttcher & Kai Ludwig & Angelique Hoelzemer & Andreas C. Hoc, 2024. "Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47741-3
    DOI: 10.1038/s41467-024-47741-3
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    References listed on IDEAS

    as
    1. Ee Lin Wong & Eric Nawrotzky & Christoph Arkona & Boo Geun Kim & Samuel Beligny & Xinning Wang & Stefan Wagner & Michael Lisurek & Dirk Carstanjen & Jörg Rademann, 2019. "The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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