Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways

• DOI: 10.1021/acsinfecdis.8b00231
• Publication Date: 2018-10-25T03:30:46Z
• Authors: Stella Hartmann; David J. Nusbaum; Kevin Kim; Saleem Alameh; Chi-Lee C. Ho; Renae L. Cruz; Anastasia Levitin; Kenneth A. Bradley; Mikhail Martchenko
• Keywords: Modulation (music)

Inflammasomes activate caspase-1 in response to molecular signals from pathogens and other dangerous stimuli as a part of the innate immune response. A previous study discovered small-molecule, 4-fluoro- N'-[1-(2-pyridinyl)ethylidene]benzohydrazide, which we named DN1, that reduces cytotoxicity anthrax lethal toxin (LT). We determined DN1 protected cells irrespectively LT concentration reduced pathogenicity an additional bacterial exotoxin several viruses. Using pathway, show does not prevent internalization catalytic activity or activation. Moreover, affect proteolytic host cathepsin B, facilitates cytoplasmic entry toxins. PubChem Bioactivities lists two G protein-coupled receptors (GPCR), type-1 angiotensin II receptor apelin receptor, targets DN1. The inhibition phosphatidylinositol 3-kinase, phospholipase C, protein kinase are downstream GPCR signaling, synergized with protecting LT. hypothesize DN1-mediated antagonism GPCRs modulates signal transduction pathways induce cellular state LT-induced pyroptosis also susceptibility Drosophila melanogaster toxin-associated infections. Future experiments will aim further characterize how inhibit pyroptotic cell death LT-sensitive macrophages. represents novel chemical probe investigate mechanisms mediate pathogenic agents.