Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response

Cheung, Nam Nam; Lai, Kin Kui; Dai, Jun; Kok, Kin Hang; Chen, Honglin; Chan, Kwok Hung; Yuen, Kwok‐Yung; Kao, Richard Yi Tsun

doi:10.1099/jgv.0.000758

Cited by 56 publications

(75 citation statements)

References 30 publications

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“…Our data are consistent with studies indicating that pyrimidine biosynthesis inhibitors do not cause the expression of IFN when applied alone, and virus growth inhibition by these drugs seems to be independent of IFN-α/β synthesis and the canonical Jak-STAT pathway (Chung et al, 2016; Lucas-Hourani et al, 2013; Lucas-Hourani et al, 2017; Wang et al, 2011; Wang et al, 2016). However, some recent reports show a lack of antiviral effect of DHODH inhibitors in Vero cells, which are deleted for the IFN-α/β gene cluster, suggesting a possible role for secreted IFNs in antiviral activity (Cheung et al, 2017). We found that SW835 activates genes involved in the innate immunity, including ISG56 (interferon-induced protein with tetratricopeptide repeats 1; encoded by IFIT1) and ISG54 (interferon-induced protein with tetratricopeptide repeats 2; encoded by IFIT2), independent of type 1 IFNs or exogenous RNA.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…So far attempts to use de novo pyrimidine inhibitors in vivo to control virus infection have met with only partial success (Bonavia et al, 2011; Cheung et al, 2017; Smee et al, 2012; Wang et al, 2011). For example, DHODH inhibitor FA-613 protected 30% of mice from lethal influenza A virus infection (Cheung et al, 2017). A77-1726, the active metabolite of the DHODH inhibitor leflunomide, reduced symptoms in respiratory syncytial virus (RSV)-infected mice, however, DHODH inhibitors administered intranasally to macaques did not suppress RSV infection (Davis et al, 2007; Grandin et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…It has been well‐established that cellular pyrimidine metabolism profoundly affects virus propagation. Dihydroorotate dehydrogenase (DHODH), an enzyme catalyzing the fourth step of de novo pyrimidine biosynthesis, was repetitively identified as the cellular target in high‐throughput screening for antivirals conducted by several groups, including us (Hoffmann et al , ; Wang et al , ; Cheung et al , ). Depletion of cellular pyrimidine inhibits the replication of an array of RNA viruses, DNA viruses, and retroviruses.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of GLDC as host susceptibility gene to severe influenza

et al. 2018

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Glycine decarboxylase (GLDC) was prioritized as a candidate susceptibility gene to severe influenza in humans. The higher expression of GLDC derived from genetic variations may confer a higher risk to H7N9 and severe H1N1 infection. We sought to characterize GLDC as functional susceptibility gene that GLDC may intrinsically regulate antiviral response, thereby impacting viral replication and disease outcome. We demonstrated that GLDC inhibitor AOAA and siRNA depletion boosted IFNβ‐ and IFN‐stimulated genes (ISGs) in combination with PolyI:C stimulation. GLDC inhibition and depletion significantly amplified antiviral response of type I IFNs and ISGs upon viral infection and suppressed the replication of H1N1 and H7N9 viruses. Consistently, GLDC overexpression significantly promoted viral replication due to the attenuated antiviral responses. Moreover, GLDC inhibition in H1N1‐infected BALB/c mice recapitulated the amplified antiviral response and suppressed viral growth. AOAA provided potent protection to the infected mice from lethal infection, comparable to a standard antiviral against influenza viruses. Collectively, GLDC regulates cellular antiviral response and orchestrates viral growth. GLDC is a functional susceptibility gene to severe influenza in humans.

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“…[107,108] Combined treatments which reduce viral replication and the host immune response to it are likely to be valuable developments. [15] A wide range of repurposed or novel potential antivirals including polymerase, nucleotide synthesis and protease inhibitors and fusion-inhibiting peptides [64,87,[109][110][111][112][113] have been investigated. [87,111] Corticosteroid use is not recommended for acute respiratory distress syndrome.…”

Section: Prevention and Treatmentmentioning

confidence: 99%

An opportunistic Pathogen Afforded Ample Opportunities: Middle East Respiratory Syndrome Coronavirus

Mackay

Arden

2017

Preprint

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The human coronaviruses (CoV) include HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1, some known for decades. The severe acute respiratory syndrome (SARS) CoV briefly emerged into the human population but was controlled. In 2012 another novel severely human pathogenic CoV -Middle Eastern Respiratory Syndrome (MERS)-CoV was identified in the Kingdom of Saudi Arabia, where 80% of over 2,000 human cases have been recorded across five years. Targeted research remains key to developing control strategies for MERS-CoV, a cause of mild illness in its camel reservoir. A new therapeutic toolbox being developed in response to MERS is also teaching us more about how CoVs cause disease. Travel-related cases continue to challenge the world's surveillance and response capabilities and more data are needed to understand unexplained primary transmission. Signs of genetic change have been recorded but it remains unclear whether any impact on clinical disease. How camels came to carry the virus remains academic to the control of MERS. To date, human-to-human transmission has been inefficient, but virus surveillance, characterisation and reporting are key to responding to any future change. MERS-CoV is not currently a pandemic threat; it is spread mainly with the aid of human habit and error.

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Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response

Abstract: Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y

Cited by 56 publications

References 30 publications

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

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

Identification and characterization of GLDC as host susceptibility gene to severe influenza

An opportunistic Pathogen Afforded Ample Opportunities: Middle East Respiratory Syndrome Coronavirus

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