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

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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 - Williams, Caroline G.

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