Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses

Priya Luthra, Jacinth Naidoo, Colette A. Pietzsch, Sampriti De, Sudip Khadka, Manu Anantpadma, Caroline G. Williams, Megan R. Edwards, Robert A. Davey, Alexander Bukreyev, Joseph M. Ready, Christopher F. Basler

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Specific host pathways that may be targeted therapeutically to inhibit the replication of Ebola virus (EBOV) and other emerging viruses remain incompletely defined. A screen of 200,000 compounds for inhibition of an EBOV minigenome (MG) assay that measures the function of the viral polymerase complex identified as hits several compounds with an amino-tetrahydrocarbazole scaffold. This scaffold was structurally similar to GSK983, a compound previously described as having broad-spectrum antiviral activity due to its impairing de novo pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase (DHODH). We generated compound SW835, the racemic version of GSK983 and demonstrated that SW835 and brequinar, another DHODH inhibitor, potently inhibit the MG assay and the replication of EBOV, vesicular stomatitis virus (VSV) and Zika (ZIKV) in vitro. Nucleoside and deoxynucleoside supplementation studies demonstrated that depletion of pyrimidine pools contributes to antiviral activity of these compounds. As reported for other DHODH inhibitors, SW835 and brequinar also induced expression of interferon stimulated genes (ISGs). ISG induction was demonstrated to occur without production of IFNα/β and independently of the IFNα receptor and was not blocked by EBOV-encoded suppressors of IFN signaling pathways. Furthermore, we demonstrated that transcription factor IRF1 is required for this ISG induction, and that IRF1 induction requires the DNA damage response kinase ATM. Therefore, de novo pyrimidine biosynthesis is critical for the replication of EBOV and other RNA viruses and inhibition of this pathway activates an ATM and IRF1-dependent innate immune response that subverts EBOV immune evasion functions.

    Original languageEnglish (US)
    Pages (from-to)288-302
    Number of pages15
    JournalAntiviral Research
    Volume158
    DOIs
    StatePublished - Oct 1 2018

    Fingerprint

    Ebolavirus
    Virus Replication
    Nucleosides
    Innate Immunity
    brequinar
    Interferons
    Antiviral Agents
    Genes
    Immune Evasion
    Vesicular Stomatitis
    RNA Viruses
    DNA Damage
    pyrimidine
    Transcription Factors
    Phosphotransferases
    Viruses
    dihydroorotate dehydrogenase

    ASJC Scopus subject areas

    • Pharmacology
    • Virology

    Cite this

    Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. / Luthra, Priya; Naidoo, Jacinth; Pietzsch, Colette A.; De, Sampriti; Khadka, Sudip; Anantpadma, Manu; Williams, Caroline G.; Edwards, Megan R.; Davey, Robert A.; Bukreyev, Alexander; Ready, Joseph M.; Basler, Christopher F.

    In: Antiviral Research, Vol. 158, 01.10.2018, p. 288-302.

    Research output: Contribution to journalArticle

    Luthra, P, Naidoo, J, Pietzsch, CA, De, S, Khadka, S, Anantpadma, M, Williams, CG, Edwards, MR, Davey, RA, Bukreyev, A, Ready, JM & Basler, CF 2018, 'Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses', Antiviral Research, vol. 158, pp. 288-302. https://doi.org/10.1016/j.antiviral.2018.08.012
    Luthra, Priya ; Naidoo, Jacinth ; Pietzsch, Colette A. ; De, Sampriti ; Khadka, Sudip ; Anantpadma, Manu ; Williams, Caroline G. ; Edwards, Megan R. ; Davey, Robert A. ; Bukreyev, Alexander ; Ready, Joseph M. ; Basler, Christopher F. / Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. In: Antiviral Research. 2018 ; Vol. 158. pp. 288-302.
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    AU - Khadka, Sudip

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    AU - Williams, Caroline G.

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    AU - Davey, Robert A.

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