JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses

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Fu , Y , Gaelings , L , Soderholm , S , Belanov , S , Nandania , J , Nyman , T A , Matikainen , S , Anders , S , Velagapudi , V & Kainov , D E 2016 , ' JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses ' , Antiviral Research , vol. 133 , pp. 23-31 . https://doi.org/10.1016/j.antiviral.2016.07.008

Title: JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses
Author: Fu, Yu; Gaelings, Lana; Soderholm, Sandra; Belanov, Sergei; Nandania, Jatin; Nyman, Tuula A.; Matikainen, Sampsa; Anders, Simon; Velagapudi, Vidya; Kainov, Denis E.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2016-09
Number of pages: 9
Belongs to series: Antiviral Research
ISSN: 0166-3542
URI: http://hdl.handle.net/10138/228312
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. (C) 2016 Elsevier B.V. All rights reserved.
Subject: HUMAN MACROPHAGES
INFECTION
GEMCITABINE
PROTEIN
SALIPHENYLHALAMIDE
1ST-IN-CLASS
EXPRESSION
KYNURENINE
BACTERIAL
OBATOCLAX
3111 Biomedicine
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