FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Sci Rep / Replication of Equine arteritis virus is efficiently suppres...
Scientific reports2020; 10(1); 10100; doi: 10.1038/s41598-020-66944-4

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

Abstract: 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.
Get Full Text
Publication Date: 2020-06-22 PubMed ID: 32572069PubMed Central: PMC7308276DOI: 10.1038/s41598-020-66944-4Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study presents a technique to test potential antiviral drugs on equine cells infected with Equine Arteritis Virus (EAV). It reveals that one existing antiviral drug and two novel inhibitors of a specific enzyme involved in DNA formation can effectively suppress the harmful effects and replication of EAV.

Method and Key Findings

The researchers adopted an in vitro (in the lab) high-throughput testing method using equine dermal cells infected by EAV. The process led to several critical findings:

  • The researchers discovered three compounds that impaired EAV infection in equine cells.
  • The first of these compounds is Ribavirin, an established broad-spectrum antiviral nucleoside analog, which has proved effective against many RNA and DNA viruses in humans and small mammals.
  • The other two are compounds known to inhibit Dihydroorotate Dehydrogenase (DHODH), the fourth enzyme in the production path of pyrimidines, a fundamental unit of DNA.
  • All three molecules suppressed the cytopathic effects associated with EAV infection, significantly inhibiting the replication of the virus and production of infectious particles.

Implications of the Research

The essential implications and potential applications of this study include:

  • Given that Ribavirin is already approved for use in humans and small animals, its proven effectiveness against EAV in this study could offer a readily available treatment option for EAV in larger mammals like horses.
  • The discovery that DHODH inhibiting compounds can suppress EAV replication promises new channels for developing antiviral treatments. With several DHODH inhibitors already in advanced clinical trials for other purposes, it may be possible to repurpose these molecules efficiently for the control of EAV.
  • The study’s findings present new possibilities for managing EAV outbreaks, especially since the vaccination coverage worldwide among equine populations is currently insufficient.
  • This research also contributes to a broader understanding of how RNA viruses operate and could lead to insights applicable to other similar viruses in animals and humans.

Cite This Article

APA
Valle-Casuso JC, Gaudaire D, Martin-Faivre L, Madeline A, Dallemagne P, Pronost S, Munier-Lehmann H, Zientara S, Vidalain PO, Hans A. (2020). Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors. Sci Rep, 10(1), 10100. https://doi.org/10.1038/s41598-020-66944-4

Publication

Scientific reports
ISSN: 2045-2322
NlmUniqueID: 101563288
Country: England
Language: English
Volume: 10
Issue: 1
Pages: 10100

Researcher Affiliations

Valle-Casuso, José-Carlos
  • Laboratoire de Santé Animale, site de Normandie de l'ANSES, PhEED Unit, 14430, Goustranville, France.
Gaudaire, Delphine
  • Laboratoire de Santé Animale, site de Normandie de l'ANSES, PhEED Unit, 14430, Goustranville, France.
Martin-Faivre, Lydie
  • Laboratoire de Santé Animale, site de Normandie de l'ANSES, PhEED Unit, 14430, Goustranville, France.
Madeline, Anthony
  • Laboratoire de Santé Animale, site de Normandie de l'ANSES, PhEED Unit, 14430, Goustranville, France.
Dallemagne, Patrick
  • Normandie Univ, UNICAEN, CERMN EA4258, 14000, Caen, France.
Pronost, Stéphane
  • LABÉO Frank Duncombe, Normandie Univ, UNICAEN, BIOTARGEN EA7450, 14280, Saint-Contest, France.
Munier-Lehmann, Hélène
  • Institut Pasteur, Unité de Chimie et Biocatalyse, CNRS UMR 3523, 75015, Paris, France.
Zientara, Stephan
  • Université Paris-Est, Laboratoire de Santé Animale, ANSES, INRA, ENVA, UMR 1161 Virologie, 94700, Maisons-Alfort, France.
Vidalain, Pierre-Olivier
  • Equipe Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes, CNRS UMR 8601, 75006, Paris, France.
  • Centre International de Recherche en Infectiologie, Univ Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, F-69007, Lyon, France.
Hans, Aymeric
  • Laboratoire de Santé Animale, site de Normandie de l'ANSES, PhEED Unit, 14430, Goustranville, France. aymeric.hans@anses.fr.

MeSH Terms

  • Animals
  • Antiviral Agents / pharmacology
  • Arterivirus Infections / drug therapy
  • Arterivirus Infections / veterinary
  • Cell Line
  • Cytopathogenic Effect, Viral / drug effects
  • Dihydroorotate Dehydrogenase
  • Equartevirus / metabolism
  • Horse Diseases / virology
  • Horses / genetics
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Purines / antagonists & inhibitors
  • Purines / biosynthesis
  • Purines / pharmacology
  • Pyrimidines / antagonists & inhibitors
  • Pyrimidines / biosynthesis
  • Pyrimidines / pharmacology
  • RNA / pharmacology
  • Ribavirin / pharmacology
  • Virus Replication / drug effects
  • Virus Replication / physiology

Conflict of Interest Statement

The authors declare no competing interests.

References

This article includes 36 references
  1. Wolf YI. Origins and Evolution of the Global RNA Virome. mBio 2018;9:e02329–02318.
    doi: 10.1128/mBio.02329-18pmc: PMC6282212pubmed: 30482837google scholar: lookup
  2. Woolhouse MEJ, Brierley L. Epidemiological characteristics of human-infective RNA viruses. Scientific Data 2018;5:180017.
    doi: 10.1038/sdata.2018.17pmc: PMC5819479pubmed: 29461515google scholar: lookup
  3. Chung DH. Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State. Antimicrob Agents Chemother 2016;60:4552–4562.
    doi: 10.1128/AAC.00282-16pmc: PMC4958224pubmed: 27185801google scholar: lookup
  4. Delekta PC. Novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo. J Virol 2014;88:11199–11214.
    doi: 10.1128/JVI.01671-14pmc: PMC4178776pubmed: 25031353google scholar: lookup
  5. Jeronimo C, Archambault D. Importance of M-protein C terminus as substrate antigen for serodetection of equine arteritis virus infection. Clinical and diagnostic laboratory immunology 2002;9:698–703.
    pmc: PMC119998pubmed: 11986280
  6. Timoney PJ, McCollum WH. Equine viral arteritis. The Veterinary clinics of North America. Equine practice 1993;9:295–309.
    doi: 10.1016/S0749-0739(17)30397-8pmc: PMC7134676pubmed: 8395325google scholar: lookup
  7. Balasuriya UBR, Carossino M, Timoney PJ. Equine viral arteritis: A respiratory and reproductive disease of significant economic importance to the equine industry. Equine Veterinary Education 2018;30:497–512.
    doi: 10.1111/eve.12672google scholar: lookup
  8. Zhang J, Stein DA, Timoney PJ, Balasuriya UB. Curing of HeLa cells persistently infected with equine arteritis virus by a peptide-conjugated morpholino oligomer. Virus research 2010;150:138–142.
    doi: 10.1016/j.virusres.2010.02.013pmc: PMC7114391pubmed: 20206215google scholar: lookup
  9. Lazic S. Serological evidence of equine arteritis virus infection and phylogenetic analysis of viral isolates in semen of stallions from Serbia. BMC Vet Res 2017;13:316.
    doi: 10.1186/s12917-017-1226-xpmc: PMC5678800pubmed: 29115996google scholar: lookup
  10. Choi J-H. Synergistic effect of ribavirin and vaccine for protection during early infection stage of foot-and-mouth disease. Journal of veterinary science 2018;19:788–797.
    doi: 10.4142/jvs.2018.19.6.788pmc: PMC6265586pubmed: 30304889google scholar: lookup
  11. Chevaliez S. Primary resistance of hepatitis B virus to nucleoside and nucleotide analogues. Journal of viral hepatitis 2019;26:278–286.
    doi: 10.1111/jvh.13025pubmed: 30339311google scholar: lookup
  12. Gotte M. Resistance to nucleotide analogue inhibitors of hepatitis C virus NS5B: mechanisms and clinical relevance. Current opinion in virology 2014;8:104–108.
    doi: 10.1016/j.coviro.2014.07.010pubmed: 25128987google scholar: lookup
  13. Topalis D. Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1. Oncotarget 2016;7:10386–10401.
    doi: 10.18632/oncotarget.7006pmc: PMC4891127pubmed: 26824416google scholar: lookup
  14. Kim Y, Lee C. Ribavirin efficiently suppresses porcine nidovirus replication. Virus Research 2013;171:44–53.
    doi: 10.1016/j.virusres.2012.10.018pmc: PMC7114464pubmed: 23108045google scholar: lookup
  15. Larrat S. Ribavirin quantification in combination treatment of chronic hepatitis C. Antimicrobial agents and chemotherapy 2003;47:124–129.
    doi: 10.1128/AAC.47.1.124-129.2003pmc: PMC149002pubmed: 12499179google scholar: lookup
  16. Lanave G. Ribavirin and boceprevir are able to reduce Canine distemper virus growth in vitro. Journal of Virological Methods 2017;248:207–211.
    doi: 10.1016/j.jviromet.2017.07.012pubmed: 28760649google scholar: lookup
  17. Ilyushina NA. Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice. Antimicrobial Agents and Chemotherapy 2008;52:3889.
    doi: 10.1128/AAC.01579-07pmc: PMC2573119pubmed: 18725448google scholar: lookup
  18. Weiss RC, Cox NR, Boudreaux MK. Toxicologic effects of ribavirin in cats. Journal of Veterinary Pharmacology and Therapeutics 1993;16:301–316.
    doi: 10.1111/j.1365-2885.1993.tb00177.xpmc: PMC7167023pubmed: 8230401google scholar: lookup
  19. Wohl BM, Smith AAA, Kryger MBL, Zelikin AN. Narrow Therapeutic Window of Ribavirin as an Inhibitor of Nitric Oxide Synthesis is Broadened by Macromolecular Prodrugs. Biomacromolecules 2013;14:3916–3926.
    doi: 10.1021/bm401048spubmed: 24156371google scholar: lookup
  20. Moreli ML, Marques-Silva AC, Pimentel VA, da Costa VG. Effectiveness of the ribavirin in treatment of hantavirus infections in the Americas and Eurasia: a meta-analysis. Virusdisease 2014;25:385–389.
    doi: 10.1007/s13337-014-0219-7pmc: PMC4188213pubmed: 25674609google scholar: lookup
  21. Nii-Trebi NI. Emerging and Neglected Infectious Diseases: Insights, Advances, and Challenges. BioMed research international 2017;2017:5245021–5245021.
    doi: 10.1155/2017/5245021pmc: PMC5327784pubmed: 28286767google scholar: lookup
  22. Leyssen P, Balzarini J, De Clercq E, Neyts J. The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. Journal of virology 2005;79:1943–1947.
    doi: 10.1128/JVI.79.3.1943-1947.2005pmc: PMC544097pubmed: 15650220google scholar: lookup
  23. Todt D. In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome. Gut 2016;65:1733.
    doi: 10.1136/gutjnl-2015-311000pmc: PMC5036239pubmed: 27222534google scholar: lookup
  24. Vignuzzi M, Stone JK, Andino R. Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications. Virus Research 2005;107:173–181.
    doi: 10.1016/j.virusres.2004.11.007pubmed: 15649563google scholar: lookup
  25. Lucas-Hourani M. Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH). Journal of medicinal chemistry 2015;58:5579–5598.
    doi: 10.1021/acs.jmedchem.5b00606pmc: PMC4516315pubmed: 26079043google scholar: lookup
  26. Lucas-Hourani M. Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. PLoS Pathog 2013;9:e1003678.
    doi: 10.1371/journal.ppat.1003678pmc: PMC3789760pubmed: 24098125google scholar: lookup
  27. Grandin C. Respiratory syncytial virus infection in macaques is not suppressed by intranasal sprays of pyrimidine biosynthesis inhibitors. Antiviral Res 2016;125:58–62.
    doi: 10.1016/j.antiviral.2015.11.006pubmed: 26593978google scholar: lookup
  28. Khatun A, Shabir N, Yoon KJ, Kim WI. Effects of ribavirin on the replication and genetic stability of porcine reproductive and respiratory syndrome virus. BMC Vet. Res. 2015;11:21.
    doi: 10.1186/s12917-015-0330-zpmc: PMC4344762pubmed: 25890207google scholar: lookup
  29. Rappe JCF. Antiviral activity of K22 against members of the order Nidovirales. Virus Res 2018;246:28–34.
    doi: 10.1016/j.virusres.2018.01.002pmc: PMC7114538pubmed: 29337162google scholar: lookup
  30. Vairo S, Van den Broeck W, Favoreel H, Scagliarini A, Nauwynck H. Development and use of a polarized equine upper respiratory tract mucosal explant system to study the early phase of pathogenesis of a European strain of equine arteritis virus. Veterinary research 2013;44:22.
    doi: 10.1186/1297-9716-44-22pmc: PMC3668984pubmed: 23537375google scholar: lookup
  31. Knecht W, Loffler M. Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem Pharmacol 1998;56:1259–1264.
    doi: 10.1016/S0006-2952(98)00145-2pubmed: 9802339google scholar: lookup
  32. Chung D. The Establishment of an Antiviral State by Pyrimidine Synthesis Inhibitor is Cell Type-Specific. Journal of antimicrobial agents 2015;1:101.
    doi: 10.4172/2472-1212.1000101pmc: PMC4936827pubmed: 27398413google scholar: lookup
  33. Falzarano D. Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013;19:1313–1317.
    doi: 10.1038/nm.3362pmc: PMC4093902pubmed: 24013700google scholar: lookup
  34. Cheung NN. Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. The Journal of general virology 2017;98:946–954.
    doi: 10.1099/jgv.0.000758pubmed: 28555543google scholar: lookup
  35. Lucas-Hourani M. Original Chemical Series of Pyrimidine Biosynthesis Inhibitors That Boost the Antiviral Interferon Response. Antimicrob Agents Chemother 61 (2017).
    pmc: PMC5610480pubmed: 28807907
  36. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat. Rev. Drug Discov. 2020;19:149–150.
    doi: 10.1038/d41573-020-00016-0pubmed: 32127666google scholar: lookup

Citations

This article has been cited 5 times.
  1. Dsouza L, Pant A, Pope B, Yang Z. Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction. J Virol 2025 Feb 25;99(2):e0211024.
    doi: 10.1128/jvi.02110-24pubmed: 39817770google scholar: lookup
  2. Dsouza L, Pant A, Pope B, Yang Z. Role of vaccinia virus growth factor in stimulating the mTORC1-CAD axis of the de novo pyrimidine pathway under different nutritional cues. bioRxiv 2024 Jul 2;.
    doi: 10.1101/2024.07.02.601567pubmed: 39005450google scholar: lookup
  3. Cochet M, Piumi F, Gorna K, Berry N, Gonzalez G, Danckaert A, Aulner N, Blanchet O, Zientara S, Donadeu FX, Munier-Lehmann H, Richardson J, Benchoua A, Coulpier M. An equine iPSC-based phenotypic screening platform identifies pro- and anti-viral molecules against West Nile virus. Vet Res 2024 Mar 16;55(1):32.
    doi: 10.1186/s13567-024-01290-1pubmed: 38493182google scholar: lookup
  4. Lozano-Terol G, Gallego-Jara J, Sola-Martínez RA, Ortega Á, Martínez Vivancos A, Cánovas Díaz M, de Diego Puente T. Regulation of the pyrimidine biosynthetic pathway by lysine acetylation of E. coli OPRTase. FEBS J 2023 Jan;290(2):442-464.
    doi: 10.1111/febs.16598pubmed: 35989594google scholar: lookup
  5. Mashin VV, Sergeev AN, Martynova NN, Oganov MD, Sergeev AA, Kataeva VV, Zagidullin NV. Ensuring Viral Safety of Equine Immunoglobulins during Production. Pharm Chem J 2022;56(2):283-288.
    doi: 10.1007/s11094-022-02632-zpubmed: 35571872google scholar: lookup
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.