Vidofludimus inhibits porcine reproductive and respiratory syndrome virus infection by targeting dihydroorotate dehydrogenase.
PRRSV infection
Vidofludimus
antiviral
broad-spectrum
dihydroorotate dehydrogenase
Journal
Veterinary research
ISSN: 1297-9716
Titre abrégé: Vet Res
Pays: England
ID NLM: 9309551
Informations de publication
Date de publication:
20 Dec 2023
20 Dec 2023
Historique:
received:
18
08
2023
accepted:
20
11
2023
medline:
21
12
2023
pubmed:
21
12
2023
entrez:
21
12
2023
Statut:
epublish
Résumé
Porcine reproductive and respiratory syndrome virus (PRRSV) infection has caused huge economic losses in global swine industry over the last 37 years. PRRSV commercial vaccines are not effective against all epidemic PRRSV strains. In this study we performed a high-throughput screening (HTS) of an FDA-approved drug library, which contained 2339 compounds, and found vidofludimus (Vi) could significantly inhibits PRRSV replication in Marc-145 cells and primary porcine alveolar macrophages (PAMs). Compounds target prediction, molecular docking analysis, and target protein interference assay showed that Vi interacts with dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in the de novo pyrimidine synthesis pathway. Furthermore, PRRSV infection was restored in the presence of excess uridine and cytidine which promote pyrimidine salvage, or excess orotate which is the product of DHODH in the de novo pyrimidine biosynthesis pathway, thus confirming that the antiviral effect of Vi against PRRSV relies on the inhibition of DHODH. In addition, Vi also has antiviral activity against Seneca virus A (SVA), encephalomyocarditis virus (EMCV), porcine epidemic diarrhea virus (PEDV), and pseudorabies virus (PRV) in vitro. These findings should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV and other swine viral infections.
Identifiants
pubmed: 38124181
doi: 10.1186/s13567-023-01251-0
pii: 10.1186/s13567-023-01251-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
124Subventions
Organisme : National Natural Science Foundation
ID : 32230103
Organisme : Jiangsu Independent Innovation Fund Project
ID : CX (22) 1006
Informations de copyright
© 2023. The Author(s).
Références
Paton DJ, Brown IH, Edwards S, Wensvoort G (1991) “Blue ear” disease of pigs. Vet Rec 128:617
pubmed: 1897099
doi: 10.1136/vr.128.26.617
Pejsak Z, Stadejek T, Markowska-Daniel I (1997) Clinical signs and economic losses caused by porcine reproductive and respiratory syndrome virus in a large breeding farm. Vet Microbiol 55:317–322
pubmed: 9220628
doi: 10.1016/S0378-1135(96)01326-0
Lunney JK, Fang Y, Ladinig A, Chen N, Li Y, Rowland B, Renukaradhya GJ (2016) Porcine Reproductive and Respiratory Syndrome Virus (PRRSV): Pathogenesis and Interaction with the Immune System. Annu Rev Anim Biosci 4:129–154
pubmed: 26646630
doi: 10.1146/annurev-animal-022114-111025
Snijder EJ, Kikkert M, Fang Y (2013) Arterivirus molecular biology and pathogenesis. J Gen Virol 94:2141–2163
pubmed: 23939974
doi: 10.1099/vir.0.056341-0
Albina E (1997) Epidemiology of porcine reproductive and respiratory syndrome (PRRS): an overview. Vet Microbiol 55:309–316
pubmed: 9220627
doi: 10.1016/S0378-1135(96)01322-3
Adams MJ, Lefkowitz EJ, King AMQ, Harrach B, Harrison RL, Knowles NJ, Kropinski AM, Krupovic M, Kuhn JH, Mushegian AR, Nibert M, Sabanadzovic S, Sanfacon H, Siddell SG, Simmonds P, Varsani A, Zerbini FM, Gorbalenya AE, Davison AJ (2017) Changes to taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2017). Arch Virol 162:2505–2538
pubmed: 28434098
doi: 10.1007/s00705-017-3358-5
Kuhn JH, Lauck M, Bailey AL, Shchetinin AM, Vishnevskaya TV, Bao Y, Ng TF, LeBreton M, Schneider BS, Gillis A, Tamoufe U, Diffo Jle D, Takuo JM, Kondov NO, Coffey LL, Wolfe ND, Delwart E, Clawson AN, Postnikova E, Bollinger L, Lackemeyer MG, Radoshitzky SR, Palacios G, Wada J, Shevtsova ZV, Jahrling PB, Lapin BA, Deriabin PG, Dunowska M, Alkhovsky SV, Rogers J, Friedrich TC, O’Connor DH, Goldberg TL (2016) Reorganization and expansion of the nidoviral family Arteriviridae. Arch Virol 161:755–768
pubmed: 26608064
doi: 10.1007/s00705-015-2672-z
Tian K, Yu X, Zhao T, Feng Y, Cao Z, Wang C, Hu Y, Chen X, Hu D, Tian X, Liu D, Zhang S, Deng X, Ding Y, Yang L, Zhang Y, Xiao H, Qiao M, Wang B, Hou L, Wang X, Yang X, Kang L, Sun M, Jin P, Wang S, Kitamura Y, Yan J, Gao GF (2007) Emergence of fatal PRRSV variants: unparalleled outbreaks of atypical PRRS in China and molecular dissection of the unique hallmark. PLoS One 2:e526
pubmed: 17565379
pmcid: 1885284
doi: 10.1371/journal.pone.0000526
Li Y, Wang X, Bo K, Wang X, Tang B, Yang B, Jiang W, Jiang P (2007) Emergence of a highly pathogenic porcine reproductive and respiratory syndrome virus in the Mid-Eastern region of China. Vet J 174:577–584
pubmed: 17869553
doi: 10.1016/j.tvjl.2007.07.032
Song J, Shen D, Cui J, Zhao B (2010) Accelerated evolution of PRRSV during recent outbreaks in China. Virus Genes 41:241–245
pubmed: 20652733
doi: 10.1007/s11262-010-0507-2
Zhang Q, Bai J, Hou H, Song Z, Zhao Y, Jiang P (2017) A novel recombinant porcine reproductive and respiratory syndrome virus with significant variation in cell adaption and pathogenicity. Vet Microbiol 208:150–158
pubmed: 28888630
doi: 10.1016/j.vetmic.2017.07.028
Vreman S, McCaffrey J, Popma-de Graaf DJ, Nauwynck H, Savelkoul HFJ, Moore A, Rebel JMJ, Stockhofe-Zurwieden N (2019) Toll-like receptor agonists as adjuvants for inactivated porcine reproductive and respiratory syndrome virus (PRRSV) vaccine. Vet Immunol Immunopathol 212:27–37
pubmed: 31213249
doi: 10.1016/j.vetimm.2019.04.008
Jeong J, Kang I, Kim S, Park SJ, Park KH, Oh T, Yang S, Chae C (2018) A modified-live porcine reproductive and respiratory syndrome virus (PRRSV)-1 vaccine protects late-term pregnancy gilts against heterologous PRRSV-1 but not PRRSV-2 challenge. Transbound Emerg Dis 65:1227–1234
pubmed: 29536637
doi: 10.1111/tbed.12862
Cruz JL, Zuniga S, Becares M, Sola I, Ceriani JE, Juanola S, Plana J, Enjuanes L (2010) Vectored vaccines to protect against PRRSV. Virus Res 154:150–160
pubmed: 20600388
doi: 10.1016/j.virusres.2010.06.017
Cui J, O’Connell CM, Costa A, Pan Y, Smyth JA, Verardi PH, Burgess DJ, Van Kruiningen HJ, Garmendia AE (2019) A PRRSV GP5-Mosaic vaccine: protection of pigs from challenge and ex vivo detection of IFNgamma responses against several genotype 2 strains. PLoS One 14:e0208801
pubmed: 30703122
pmcid: 6354972
doi: 10.1371/journal.pone.0208801
Oh T, Kim H, Park KH, Jeong J, Kang I, Yang S, Chae C (2019) Effectiveness of a commercial porcine reproductive and respiratory syndrome virus (PRRSV) subunit vaccine against heterologous PRRSV-1 and PRRSV-2 challenge in late-term pregnant gilts. Can J Vet Res 83:248–254
pubmed: 31571723
pmcid: 6753889
Renukaradhya GJ, Meng XJ, Calvert JG, Roof M, Lager KM (2015) Inactivated and subunit vaccines against porcine reproductive and respiratory syndrome: current status and future direction. Vaccine 33:3065–3072
pubmed: 25980425
doi: 10.1016/j.vaccine.2015.04.102
Murtaugh MP, Genzow M (2011) Immunological solutions for treatment and prevention of porcine reproductive and respiratory syndrome (PRRS). Vaccine 29:8192–8204
pubmed: 21925560
doi: 10.1016/j.vaccine.2011.09.013
Charerntantanakul W (2012) Porcine reproductive and respiratory syndrome virus vaccines: Immunogenicity, efficacy and safety aspects. World J Virol 1:23–30
pubmed: 24175208
pmcid: 3782261
doi: 10.5501/wjv.v1.i1.23
Zhang M, Wu Q, Chen Y, Duan M, Tian G, Deng X, Sun Y, Zhou T, Zhang G, Chen W, Chen J (2018) Inhibition of proanthocyanidin A2 on porcine reproductive and respiratory syndrome virus replication in vitro. PLoS ONE 13:e0193309
pubmed: 29489892
pmcid: 5831109
doi: 10.1371/journal.pone.0193309
Li L, Tian X, Chen J, Li P, Zheng Q, Hou J (2018) Griffithsin inhibits porcine reproductive and respiratory syndrome virus infection in vitro. Arch Virol 163:3317–3325
pubmed: 30220033
pmcid: 7087274
doi: 10.1007/s00705-018-4029-x
Ge M, Xiao Y, Chen H, Luo F, Du G, Zeng F (2018) Multiple antiviral approaches of (-)-epigallocatechin-3-gallate (EGCG) against porcine reproductive and respiratory syndrome virus infection in vitro. Antiviral Res 158:52–62
pubmed: 30048655
doi: 10.1016/j.antiviral.2018.07.012
Wang X, Dong W, Zhang X, Zhu Z, Chen Y, Liu X, Guo C (2021) antiviral mechanism of tea polyphenols against porcine reproductive and respiratory syndrome virus. Pathogens 10:202
pubmed: 33668502
pmcid: 7917843
doi: 10.3390/pathogens10020202
Xu Z, Huang M, Xia Y, Peng P, Zhang Y, Zheng S, Wang X, Xue C, Cao Y (2021) Emodin from Aloe inhibits Porcine reproductive and respiratory syndrome virus via Toll-like receptor 3 activation. Viruses 13:1243
pubmed: 34206896
pmcid: 8310261
doi: 10.3390/v13071243
Chen X, Bai J, Liu X, Song Z, Zhang Q, Wang X, Jiang P (2018) Nsp1α of porcine reproductive and respiratory syndrome virus strain BB0907 impairs the function of monocyte-derived dendritic cells via the release of soluble CD83. J Virol 92:e00366-18
pubmed: 29793955
pmcid: 6052304
doi: 10.1128/JVI.00366-18
PubChem database. https://pubchem.ncbi.nlm.nih.gov . Accessed 3 Feb 2021
SwissTargetPrediction. http://www.swisstargetprediction.ch . Accessed 3 Feb 2021
Daina A, Michielin O, Zoete V (2019) SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 47:W357–W364
pubmed: 31106366
pmcid: 6602486
doi: 10.1093/nar/gkz382
SWISS-MODEL. https://swissmodel.expasy.org . Accessed 5 Feb 2021
SAVES v6.0. https://saves.mbi.ucla.edu . Accessed 5 Feb 2021
ProSA-web. https://prosa.services.came.sbg.ac.at/prosa.php . Accessed 5 Feb 2021
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35:W407-410
pubmed: 17517781
pmcid: 1933241
doi: 10.1093/nar/gkm290
Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718
pubmed: 16211538
doi: 10.1002/jcc.20291
Abraham MJ, Murtola T, Schulz R, Páll S, C. Smith J, Hess B, Lindahl E, (2015) GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1:19–25
doi: 10.1016/j.softx.2015.06.001
Ahammad F, Alam R, Mahmud R, Akhter S, Talukder EK, Tonmoy AM, Fahim S, Al-Ghamdi K, Samad A, Qadri I (2021) Pharmacoinformatics and molecular dynamics simulation-based phytochemical screening of neem plant (Azadiractha indica) against human cancer by targeting MCM7 protein. Brief Bioinform 22:bbab098
pubmed: 33834183
doi: 10.1093/bib/bbab098
Zheng Y, Li S, Song K, Ye J, Li W, Zhong Y, Feng Z, Liang S, Cai Z, Xu K (2022) A broad antiviral strategy: inhibitors of human DHODH pave the way for host-targeting antivirals against emerging and re-emerging viruses. Viruses 14:928
pubmed: 35632670
pmcid: 9146014
doi: 10.3390/v14050928
Amadori M, Listorti V, Razzuoli E (2021) Reappraisal of PRRS immune control strategies: the way forward. Pathogens 10:1073
pubmed: 34578106
pmcid: 8469074
doi: 10.3390/pathogens10091073
Rusai K, Schmaderer C, Baumann M, Chmielewski S, Prokai A, Kis E, Szabo AJ, Leban J, Doblhofer R, Ammendola A, Lutz J, Heemann U (2012) Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation. Transplantation 93:1101–1107
pubmed: 22609757
doi: 10.1097/TP.0b013e31824fd861
Fitzpatrick LR, Small JS, Doblhofer R, Ammendola A (2012) Vidofludimus inhibits colonic interleukin-17 and improves hapten-induced colitis in rats by a unique dual mode of action. J Pharmacol Exp Ther 342:850–860
pubmed: 22691298
doi: 10.1124/jpet.112.192203
Hahn F, Wangen C, Hage S, Peter AS, Dobler G, Hurst B, Julander J, Fuchs J, Ruzsics Z, Uberla K, Jack HM, Ptak R, Muehler A, Groppel M, Vitt D, Peelen E, Kohlhof H, Marschall M (2020) IMU-838, a developmental DHODH inhibitor in phase II for autoimmune disease, shows anti-SARS-CoV-2 and broad-spectrum antiviral efficacy in vitro. Viruses 12:1394
pubmed: 33291455
pmcid: 7762174
doi: 10.3390/v12121394
Kulkarni OP, Sayyed SG, Kantner C, Ryu M, Schnurr M, Sardy M, Leban J, Jankowsky R, Ammendola A, Doblhofer R, Anders HJ (2010) 4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice. Am J Pathol 176:2840–2847
pubmed: 20413687
pmcid: 2877845
doi: 10.2353/ajpath.2010.091227
Muehler A, Peelen E, Kohlhof H, Groppel M, Vitt D (2020) Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 43:102129
pubmed: 32428844
doi: 10.1016/j.msard.2020.102129
Tang H, Liu Y, Ren R, Liu Y, He Y, Qi Z, Peng H, Zhao P (2022) Identification of clinical candidates against West Nile virus by activity screening in vitro and effect evaluation in vivo. J Med Virol 94:4918–4925
pubmed: 35644833
doi: 10.1002/jmv.27891
Hoffmann HH, Kunz A, Simon VA, Palese P, Shaw ML (2011) Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis. Proc Natl Acad Sci U S A 108:5777–5782
pubmed: 21436031
pmcid: 3078400
doi: 10.1073/pnas.1101143108
Yang CF, Gopula B, Liang JJ, Li JK, Chen SY, Lee YL, Chen CS, Lin YL (2018) Novel AR-12 derivatives, P12–23 and P12–34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis. Emerg Microbes Infect 7:187
pubmed: 30459406
pmcid: 6246607
doi: 10.1038/s41426-018-0191-1
Marschall M, Niemann I, Kosulin K, Bootz A, Wagner S, Dobner T, Herz T, Kramer B, Leban J, Vitt D, Stamminger T, Hutterer C, Strobl S (2013) Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis. Antiviral Res 100:640–648
pubmed: 24149002
doi: 10.1016/j.antiviral.2013.10.003
Cheung NN, Lai KK, Dai J, Kok KH, Chen H, Chan KH, Yuen KY, Kao RYT (2017) Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response. J Gen Virol 98:946–954
pubmed: 28555543
doi: 10.1099/jgv.0.000758
Guo C, Zhu Z, Guo Y, Wang X, Yu P, Xiao S, Chen Y, Cao Y, Liu X (2017) Heparanase upregulation contributes to porcine reproductive and respiratory syndrome virus release. J Virol 91:e00625-17
pubmed: 28490587
pmcid: 5512235
doi: 10.1128/JVI.00625-17
Wang R, Wang X, Ni B, Huan CC, Wu JQ, Wen LB, Liao Y, Tong GZ, Ding C, Fan HJ, Mao X (2016) Syndecan-4, a PRRSV attachment factor, mediates PRRSV entry through its interaction with EGFR. Biochem Biophys Res Commun 475:230–237
pubmed: 27208778
doi: 10.1016/j.bbrc.2016.05.084
Burkard C, Lillico SG, Reid E, Jackson B, Mileham AJ, Ait-Ali T, Whitelaw CB, Archibald AL (2017) Precision engineering for PRRSV resistance in pigs: macrophages from genome edited pigs lacking CD163 SRCR5 domain are fully resistant to both PRRSV genotypes while maintaining biological function. PLoS Pathog 13:e1006206
pubmed: 28231264
pmcid: 5322883
doi: 10.1371/journal.ppat.1006206