title: Obatoclax, saliphenylhalamide and gemcitabine inhibit Zika virus infection in vitro and differentially affect cellular signaling, transcription and metabolism.
abstract: An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are no approved therapies to treat this emerging viral disease. Here, we tested three cell-directed broad-spectrum antiviral compounds against ZIKV replication using human retinal pigment epithelial (RPE) cells and a low-passage ZIKV strain isolated from fetal brain. We found that obatoclax, SaliPhe, and gemcitabine inhibited ZIKV infections at noncytotoxic concentrations. Moreover, all three compounds prevented production of viral RNA and proteins as well as activation of cellular caspase 8, 3 and 7. However, these compounds differentially affected ZIKV-mediated transcription, translation and posttranslational modifications of cellular factors as well as metabolic pathways indicating that these agents possess different mechanisms of action. Interestingly, combination of obatoclax and SaliPhe at nanomolar concentrations had a synergistic effect against ZIKV infection. Thus, our results provided the foundation for development of broad-spectrum cell-directed antivirals or their combinations for treatment of ZIKV and other emerging viral diseases.
authors.affiliation: Department of Virology, Medicum, University of Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Kuivanen
authors.affiliation: Department of Molecular Neurology, Biomedicum Stem Cells Center Research Program Unit, University of Helsinki, Finland.
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Bespalov
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland.
authors.forename: Jatin
authors.initials: J
authors.lastname: Nandania
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Ianevski
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland.
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, USA; Department of Virology and Immunology, University of Helsinki and Helsinki University Hospital, Finland.
authors.forename: Jef K
authors.initials: JK
authors.lastname: De Brabander
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland. Electronic address: denis.kainov@helsinki.fi.
authors.forename: Denis E
authors.initials: DE
authors.lastname: Kainov
authors.affiliation: Department of Virology, Medicum, University of Helsinki, Finland; Department of Virology and Immunology, University of Helsinki and Helsinki University Hospital, Finland; Department of Veterinary Biosciences, University of Helsinki, Finland. Electronic address: olli.vapalahti@helsinki.fi.
authors.forename: Olli
authors.initials: O
authors.lastname: Vapalahti
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D020169:Caspases / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus / Q000033:anatomy & histology; D006801:Humans; D007211:Indoles; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D012367:RNA, Viral / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000821:virology; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000577:Amides; D000998:Antiviral Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D012367:RNA, Viral; D012459:Salicylates; C574373:saliphenylhalamide; D003841:Deoxycytidine; D020169:Caspases; C520962:obatoclax; D000093542:Gemcitabine