title: JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses.
abstract: JNJ-63623872 (formally known as VX-787; referred to here as JNJ872) is an orally bioavailable compound, which is in phase II clinical trials for the treatment of influenza A virus (IAV) infections. Here we show that JNJ872 inhibits at nanomolar concentrations the transcription of viral RNA in IAV-infected human macrophages by targeting a highly conserved site on the cap-snatching domain of influenza polymerase basic 2 protein (PB2). Furthermore, even lower concentrations of JNJ872 protected macrophages from IAV-mediated death when given in combination with 100 nM gemcitabine, which also attenuated transcription and replication of viral RNA. Importantly, treating human macrophages with JNJ872 allowed expression of many immune-related and other genes, involved in antiviral responses, such as indoleamine 2,3-dioxygenase 1 (IDO), and cytosolic 5'-nucleotidase 3A (NT5C3A). Moreover, our targeted metabolomics analysis indicate that treatment with JNJ782 did not interfere with metabolic responses to infection, which further supported our transcriptomics results. Thus, VX-737 alone or in combination with other drugs could be beneficial for treating IAV infected patients, because it would allow the development of antiviral responses and, thereby, protect individuals from current and future infections with closely related IAV strains.
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Lana
authors.initials: L
authors.lastname: Gaelings
authors.affiliation: Institute of Biotechnology (BI), University of Helsinki, Finland; Finnish Institute of Occupational Health (TTL), Helsinki, Finland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Söderholm
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Sergei
authors.initials: S
authors.lastname: Belanov
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Jatin
authors.initials: J
authors.lastname: Nandania
authors.affiliation: Institute of Biotechnology (BI), University of Helsinki, Finland.
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.affiliation: Finnish Institute of Occupational Health (TTL), Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Simon
authors.initials: S
authors.lastname: Anders
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.affiliation: The 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
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology*; D007251:Influenza, Human / Q000235:genetics / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase