Structure-Based Design and Synthesis of Covalent Inhibitors for Deubiquitinase and Acetyltransferase ChlaDUB1 of Chlamydia trachomatis

  • J Med Chem. 2024 Jun 19. doi: 10.1021/acs.jmedchem.4c00230.
Thomas Zimmermann  1 ,  Jiachen Feng  2 ,  Luana Janaína de Campos  2 ,  Lindsey A Knight  3 ,  Jan Schlötzer  4 ,  Yesid A Ramirez  1 ,  Kevin Schwickert  5 ,  Markus Zehe  1 ,  Thomas B Adler  1 ,  Tanja Schirmeister  5 ,  Caroline Kisker  4 ,  Christoph Sotriffer  1 ,  Martin Conda-Sheridan  2 ,  Michael Decker  1
Affiliations
  • 1. Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg (JMU), Am Hubland, 97074 Würzburg, Germany.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 3. Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 4. Rudolf Virchow Center for Integrative and Translational Bioimaging, Institute for Structural Biology, Julius-Maximilians-Universität Würzburg (JMU), 97080 Wurzburg, Germany.
  • 5. Institute of Pharmaceutical and Biomedical Sciences (IPBS), Johannes Gutenberg University Mainz, Staudingerweg 5, 55128 Mainz, Germany.
PMID: 38897928 DOI: 10.1021/acs.jmedchem.4c00230
Abstract

Upon Infection by an intracellular pathogen, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen Chlamydia trachomatis, a major cause of trachoma and sexually transmitted diseases, depends on the suppression of host cell Apoptosis. C. trachomatis secretes Deubiquitinase ChlaDUB1 into the host cell, leading among Other interactions to the stabilization of antiapoptotic proteins and, thus, suppression of host cell Apoptosis. Targeting the Bacterial effector protein may, therefore, lead to new therapeutic possibilities. To explore the active site of ChlaDUB1, an iterative cycle of computational docking, synthesis, and enzymatic screening was applied with the aim of lead structure development. Hereby, covalent inhibitors were developed, which show enhanced inhibition with a 22-fold increase in IC50 values compared to previous work. Comprehensive insights into the binding prerequisites to ChlaDUB1 are provided, establishing the foundation for an additional specific antichlamydial therapy by small molecules.

Products