title: Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus.
abstract: Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2,000 bioactive compounds for their ability to block Zika virus infection in three distinct cell types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA-approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition. Importantly, we identified nanchangmycin as a potent inhibitor of Zika virus entry across all cell types tested, including physiologically relevant primary cells. Nanchangmycin also was active against other medically relevant viruses, including West Nile, dengue, and chikungunya viruses that use a similar route of entry. This study provides a resource of small molecules to study Zika virus pathogenesis.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Rausch
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Hackett
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Weinbren
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sophia M
authors.initials: SM
authors.lastname: Reeder
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 19104, USA; Department of Obstetrics, Gynecology, and Reproductive Science, University of Pittsburgh, Pittsburgh, PA 19104, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 19104, USA.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Sadovsky
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.affiliation: High-Throughput Screening Core, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Schultz
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 19104, USA; Department of Obstetrics, Gynecology, and Reproductive Science, University of Pittsburgh, Pittsburgh, PA 19104, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 19104, USA.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: cherrys@mail.med.upenn.edu.
authors.forename: Sara
authors.initials: S
authors.lastname: Cherry
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002646:Chikungunya virus / Q000187:drug effects; D003716:Dengue Virus / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000821:virology; D004987:Ethers / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D014327:Trophoblasts / Q000166:cytology / Q000821:virology; D053586:Virus Internalization / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D004987:Ethers; D009705:Nucleosides; D054852:Small Molecule Libraries; D013141:Spiro Compounds; C452419:nanchangmycin
keywords: antivirals; arbovirus; drugs; entry; flavivirus; repurposing; therapeutics