Original Chemical Series of Pyrimidine Biosynthesis Inhibitors That Boost the Antiviral Interferon Response

Lucas‐Hourani, Marianne; Dauzonne, Daniel; Munier‐Lehmann, Hélène; Khiar, Samira; Nisole, Sébastien; Dairou, Julien; Helynck, Olivier; Afonso, Philippe V.; Tangy, Frédéric; Vidalain, Pierre‐Olivier

doi:10.1128/aac.00383-17

Cited by 25 publications

(20 citation statements)

References 35 publications

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“…Depletion of cellular pyrimidine inhibits the replication of an array of RNA viruses, DNA viruses, and retroviruses. Interestingly, Lucas‐Hourani et al (, ) reported that pyrimidine deprivation suppresses viral growth through amplifying innate immune response, rather than depleting nucleotide precursors for viral genome replication as assumed previously (Hoffmann et al , ). Consolidating prior knowledge and the findings of genetic association studies, we hypothesized a link between GLDC and innate immunity, which may impact viral growth and underlie the genetic association of GLDC with H7N9 and severe H1N1 infection.…”

Section: Introductionmentioning

confidence: 73%

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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Section: Introductionmentioning

confidence: 73%

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

et al. 2018

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“…GSK983 and other inhibitors of pyrimidine biosynthesis induce expression of ISGs, the expression of which can be induced by the antiviral cytokines known as IFNs (Harvey et al, 2009; Lucas-Hourani et al, 2013; Lucas-Hourani et al, 2017). Given that ISGs mediate the antiviral effects of IFNs, it was of interest to determine how SW835 and brequinar induce ISG expression and to what extent this contributes to the antiviral effects of these compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Beyond suppression of viral RNA synthesis, DHODH inhibitors have been demonstrated to trigger expression of ISGs, an activity that may also contribute to the antiviral effects of these compounds (Chung et al, 2016; Lucas-Hourani et al, 2013; Wang et al, 2016). Mechanistically, these compounds may not require IFN production for ISG induction but may induce ISGs through activation of the transcription factor Interferon Regulatory Factor 1 (IRF1) (Chung et al, 2016; Lucas-Hourani et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

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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“…Additionally, we showed that the DHODH inhibitors GAC50 and IPPA17-A04 also impair the replication of EAV, with IPPA17-A04 outperforming ribavirin and GAC50 as assessed by a higher selectivity index. It is known that Coronaviridae are inhibited by drugs targeting de novo pyrimidine biosynthesis, including HCoV-229E, MERS-CoV and SARS-CoV, and DHODH inhibitors were in the list of therapeutic options to be tested against SARS-CoV-2 [34][35][36] . Our results demonstrate that this antiviral activity extends to Arteriviridae, suggesting that pyrimidine biosynthesis inhibitors may act as pan-nidovirales inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

Valle-Casuso

Gaudaire

Martin-Faivre

et al. 2020

Sci Rep

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RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two vaccines are available, the vaccination coverage of the equine population is largely insufficient to prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly inhibited viral replication and production of infectious particles. Since ribavirin is already approved in human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results open new perspectives for the management of EAV outbreaks. Viruses with a RNA genome infect both animals and plants, and dominate the eukaryotic virome by their diversity and deleterious effects 1. Indeed, RNA viral infections are a substantial public health burden affecting humans and domestic animals 2. The pandemic of SARS-CoV-2 coronavirus is the latest and most striking example with thousands of deaths reported so far in different countries in the world. Horses are not an exception, and five of seven equine viruses listed by the World Organization for Animal Health are RNA viruses (OIE). Unfortunately, the veterinary therapeutic arsenal to fight against equine viral diseases is limited, or even not-existent as no antiviral molecule is listed today. During the last years, several studies have used high-throughput screening (HTS) techniques to scan small compound libraries that could impair the replication of equine viruses. These studies were mostly focused on zoonotic viruses like West-Nile virus 3,4. Non-zoonotic equine RNA viruses, such as equine arteritis virus (EAV), were not included in those screenings. Equine arteritis virus (EAV) is a positive-sense single-stranded RNA virus, member of the subfamily Equarterivirinae, member of the family Arteriviridae, genus Alphaarterivirus from order Nidovirales like the Coronaviridae. Equine viral arteritis disease is a recurrent viral infection that causes important economic losses to the horse industry. In most of the cases, EAV infection is subclinical, but some viral strains are virulent and induce fever with body temperature going up to 41 °C, depression, anorexia, edema, nasal discharge, and conjunctivitis. EAV is a virus transmitted by respiratory or venereal routes.

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Original Chemical Series of Pyrimidine Biosynthesis Inhibitors That Boost the Antiviral Interferon Response

Cited by 25 publications

References 35 publications

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

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

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

Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

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