دانلود رایگان مقاله JNJ872 مهار تکثیر ویروس آنفولانزای A

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.

5. Conclusion

JNJ872 targets an evolutionary conserved site on influenza polymerase subunit PB2 and inhibits the transcription of viral genes. Moreover, a treatment with JNJ872 allowed the transcription of a set of cellular antiviral genes, and translation of cytokines and other antiviral proteins involved in the tryptophan or nucleotide metabolism. Furthermore, the combination of JNJ872 with gemcitabine protected human macrophages from IAV-mediated death at substantially lower concentrations than that of the compounds alone. VX-737 alone or in combination with other drugs, which inhibit IAV but allow development of antiviral responses, could be beneficial for treating IAV infected patients, because it would mount resistance to reinfections.