2. Academic Validation
  3. Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins

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

  • Nat Commun. 2024 Apr 26;15(1):3537. doi: 10.1038/s41467-024-47741-3.
Umer Bin Abdul Aziz # 1,  Ali Saoud # 1,  Marcel Bermudez 1 2,  Maren Mieth 3,  Amira Atef 1 4,  Thomas Rudolf 1,  Christoph Arkona 1,  Timo Trenkner 5,  Christoph Böttcher 6,  Kai Ludwig 6,  Angelique Hoelzemer 5 7,  Andreas C Hocke 3,  Gerhard Wolber 1,  Jörg Rademann 8
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany.
  • 2 Institute for Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149, Münster, Germany.
  • 3 Department of Infectious Diseases, Respiratory Medicine, and Critical Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Assuit University, Assiut, 71526, Egypt.
  • 5 Leibniz Institute of Virology, Hamburg, 20251, Germany.
  • 6 Institute of Chemistry and Biochemistry, Research Center of Electron Microscopy (FZEM), Freie Universität Berlin, Fabeckstraße 36A, 14195, Berlin, Germany.
  • 7 First Department of Medicine, University Medical Center Hamburg-Eppendorf (UKE), 20251, Hamburg, Germany.
  • 8 Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany. joerg.rademann@fu-berlin.de.
  • # Contributed equally.
PMID: 38670939 DOI: 10.1038/s41467-024-47741-3
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.

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