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.

Multi-Omics Studies towards Novel Modulators of Influenza A Virus-Host Interaction

“…[10][11][12][13]. These molecules should be first evaluated in vitro using antiviral efficacy assays, and then in animal models as described in our previous studies [14].…”

“…In particular, our recent transcriptomics study identified a total of 126 genes which were up-or down-regulated greater than four-fold in A/Udorn/1972(H3N2) or A/WSN/1933(H1N1) virus infected human peripheral blood mononuclear cells (PBMC)-derived macrophages compared to mock-infected cells at 8 h post infection (p < 0.05) [10]. The most significant canonical pathways specifically associated with virus infections, according to gene set enrichment analysis (GSEA; www.broadinstitute.org/gsea, [16]), were interferon-α, -β, and -γ signaling, cytokine signaling, [10][11][12][13].…”

“…The most significant canonical pathways specifically associated with virus infections, according to gene set enrichment analysis (GSEA; www.broadinstitute.org/gsea, [16]), were interferon-α, -β, and -γ signaling, cytokine signaling, [10][11][12][13]. These molecules should be first evaluated in vitro using antiviral efficacy assays, and then in animal models as described in our previous studies [14].…”

“…We also observed alterations in glutathione, nitrogen, arginine and proline, alanine, asparagine and glutamine, histamine, cysteine and methionine metabolic pathways. The molecules (which are all enzymes) identified in the metabolomics study [10] and which are involved in these pathways, were manually examined in the KEGG database [19]. Several compounds targeting these enzymes were then identified using the Drug Bank database [17].…”

Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis

“…IAV also actively exploits cell metabolism for the production of viral RNA, proteins, and lipids [24,26,[31][32][33][34][35][36]. Free NTPs are used by viral polymerase which produces vRNA and its replication intermediates.…”