title: Discovery of host-targeted covalent inhibitors of dengue virus.
abstract: We report here on an approach targeting the host reactive cysteinome to identify inhibitors of host factors required for the infectious cycle of Flaviviruses and other viruses. We used two parallel cellular phenotypic screens to identify a series of covalent inhibitors, exemplified by QL-XII-47, that are active against dengue virus. We show that the compounds effectively block viral protein expression and that this inhibition is associated with repression of downstream processes of the infectious cycle, and thus significantly contributes to the potent antiviral activity of these compounds. We demonstrate that QL-XII-47's antiviral activity requires selective, covalent modification of a host target by showing that the compound's antiviral activity is recapitulated when cells are preincubated with QL-XII-47 and then washed prior to viral infection and by showing that QL-XII-47R, a non-reactive analog, lacks antiviral activity at concentrations more than 20-fold higher than QL-XII-47's IC90. QL-XII-47's inhibition of Zika virus, West Nile virus, hepatitis C virus, and poliovirus further suggests that it acts via a target mediating inhibition of these other medically relevant viruses. These results demonstrate the utility of screens targeting the host reactive cysteinome for rapid identification of compounds with potent antiviral activity.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mélissanne
authors.initials: M
authors.lastname: de Wispelaere
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Margot
authors.initials: M
authors.lastname: Carocci
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vetter
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: priscilla_yang@hms.harvard.edu.
authors.forename: Priscilla L
authors.initials: PL
authors.lastname: Yang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects*; D055808:Drug Discovery; D005416:Flavivirus / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D014779:Virus Replication / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents