High-Throughput Screen in Identifies a Novel Molecular Scaffold That Inhibits Cell Wall Integrity Pathway Signaling.

Journal: ACS infectious diseases
Published Date: Nov 6, 2015

Abstract

is one of the most important human fungal pathogens; however, no new therapies have been developed in over 50 years. Fungicidal activity is crucially important for an effective anticryptococal agent and, therefore, we screened 361,675 molecules against using an adenylate kinase release assay that specifically detects fungicidal activity. A set of secondary assays narrowed the set of hits to molecules that interfere with fungal cell wall integrity and identified three benzothioureas with low in vitro mammalian toxicity and good in vitro anticryptococcal (minimum inhibitory concentration = 4 μg/mL). This scaffold inhibits signaling through the cell wall integrity MAP kinase cascade. Structure-activity studies indicate that the thiocarbonyl moiety is crucial for activity. Genetic and biochemical data suggest that benzothioureas inhibit signaling upstream of the kinase cascade. Thus, the benzothioureas appear to be a promising new scaffold for further exploration in the search for new anticryptococcal agents.

Authors

  • Kate Hartland
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Jun Pu
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Michelle Palmer
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Sivaraman Dandapani
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Philip N Moquist
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Benito Munoz
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Louis DiDone
    Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
  • Stuart L Schreiber
    Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Damian J Krysan
    Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, United States; Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, United States.

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