Veterinary Research Communications

, Volume 42, Issue 4, pp 309–313 | Cite as

The IMPDH inhibitors, ribavirin and mycophenolic acid, inhibit peste des petits ruminants virus infection

  • Qiu-yan Chang
  • Fu-cheng Guo
  • Xue-rui Li
  • Jian-hua ZhouEmail author
  • Xuepeng Cai
  • Qiuwei Pan
  • Xiao-xia MaEmail author


Peste des petits ruminants virus (PPRV) causes highly contagious diseases in domestic and particular wild small ruminants, leading to substantial economic loss. The development of effective and cheap antiviral medications shall help to circumvent this emerging burden. In this study, we found that ribavirin, a competitive inosine-5’-monophosphate dehydrogenase (IMPDH) inhibitor, significantly inhibits the replication of PPRV. As IMPDH is a key enzyme in purine nucleotide synthesis, supplementation of exogenous guanosine attenuate the anti-PPRV effect of ribavirin. Interestingly, an uncompetitive IMPDH inhibitor, mycophenolic acid (MPA), exerted more potent antiviral effect again PPRV. Similarly, this effect was largely restored upon supplementation of guanosine. Thus, we have demonstrated that the IMPDH inhibitors ribavirin and MPA combat PPRV infection through purine nucleotide depletion. Because both regimens have been widely used in the clinic for treating viral infection or organ rejection in transplantation patients for decades, respectively, repurposing these existing safe and cheap medications may provide a new avenue for combating PPRV infection.



The authors would like to thank Dr. Qiuwei Pan (Erasmus MC-University Medical Center) for helpful technical assistance. This study was funded by Key science and Technology Foundation of Gansu Province (1504WKCA094), Characteristic discipline of bioengineering construction for the special guide project of the world class universities and world-class disciplines of Northwest Minzu University(10018703), and National Natural Science foundation of China (No.31302100).

Compliance with ethical standards

In this study, all experiments have carried out without any humans or animals.

Conflict of interest

All authors have no conflict of interest in this study.


  1. Bao J, Wang Z, Li L, Wu X, Sang P, Wu G, Ding G, Suo L, Liu C, Wang J, Zhao W, Li J, Qi L (2011) Detection and genetic characterization of peste des petits ruminants virus in free-living bharals (Pseudois nayaur) in Tibet, China. Res Vet Sci 90:238–240CrossRefGoogle Scholar
  2. Bao J, Wang Q, Li L, Liu C, Zhang Z, Li J, Wang S, Wu X, Wang Z (2017) Evolutionary dynamics of recent peste des petits ruminants virus epidemic in China during 2013-2014. Virology 510:156–164CrossRefGoogle Scholar
  3. Baron MD, Diop B, Njeumi F, Willett BJ, Bailey D (2017) Future research to underpin successful peste des petits ruminants virus (PPRV) eradication. J Gen Virol 98:2635–2644CrossRefGoogle Scholar
  4. Borden KL, Culjkovic-Kraljacic B (2010) Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma 51:1805–1815CrossRefGoogle Scholar
  5. Casey J, Morris K, Narayana M, Nakagaki M, Kennedy GA (2013) Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 48:1558–1561CrossRefGoogle Scholar
  6. Cholongitas E, Papatheodoridis GV (2014) Sofosbuvir: a novel oral agent for chronic hepatitis C. Ann Gastroenterol 27:331–337PubMedPubMedCentralGoogle Scholar
  7. Dang W, Yin Y, Wang Y, Wang W, Su J, Sprengers D, van der Laan LJW, Felczak K, Pankiewicz KW, Chang KO, Koopmans MPG, Metselaar HJ, Peppelenbosch MP, Pan Q (2017) Inhibition of Calcineurin or IMP dehydrogenase exerts moderate to potent antiviral activity against norovirus replication. Antimicrob Agents Chemother 61Google Scholar
  8. Dao Thi VL, Debing Y, Wu X, Rice CM, Neyts J, Moradpour D, Gouttenoire J (2016) Sofosbuvir inhibits hepatitis E virus replication in vitro and results in an additive effect when combined with ribavirin. Gastroenterology 150(82–85):e84Google Scholar
  9. Debing Y, Winton J, Neyts J, Dallmeier K (2013) Cutthroat trout virus as a surrogate in vitro infection model for testing inhibitors of hepatitis E virus replication. Antivir Res 100:98–101CrossRefGoogle Scholar
  10. Debing Y, Gisa A, Dallmeier K, Pischke S, Bremer B, Manns M, Wedemeyer H, Suneetha PV, Neyts J (2014) A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients. Gastroenterology 147:1008–1011CrossRefGoogle Scholar
  11. Diallo A (2004) Vaccination for the control of peste des petits ruminants. Dev Biol (Basel) 119:93–98Google Scholar
  12. Dixit NM, Perelson AS (2006) The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus. Cell Mol Life Sci 63:832–842CrossRefGoogle Scholar
  13. Dong C, Zafrullah M, Mixson-Hayden T, Dai X, Liang J, Meng J, Kamili S (2012) Suppression of interferon-alpha signaling by hepatitis E virus. Hepatology 55:1324–1332CrossRefGoogle Scholar
  14. Graci JD, Cameron CE (2006) Mechanisms of action of ribavirin against distinct viruses. Rev Med Virol 16:37–48CrossRefGoogle Scholar
  15. Jain A, Vekatramanan R, Yelochan B, Kashyap R, Marcos A, Fung J (2005) Ribavirin levels in post liver transplant patients treated for recurrent hepatitis C viral infection. Transplant Proc 37:3190–3196CrossRefGoogle Scholar
  16. Kihira S, Uematsu J, Kawano M, Itoh A, Ookohchi A, Satoh S, Maeda Y, Sakai K, Yamamoto H, Tsurudome M, O'Brien M, Komada H (2014) Ribavirin inhibits human parainfluenza virus type 2 replication in vitro. Microbiol Immunol 58:628–635CrossRefGoogle Scholar
  17. Lanave G, Cavalli A, Martella V, Fontana T, Losappio R, Tempesta M, Decaro N, Buonavoglia D, Camero M (2017) Ribavirin and boceprevir are able to reduce canine distemper virus growth in vitro. J Virol Methods 248:207–211CrossRefGoogle Scholar
  18. Li W, Jin H, Sui X, Zhao Z, Yang C, Wang W, Li J, Li G (2014) Self-assembly and release of peste des petits ruminants virus-like particles in an insect cell-baculovirus system and their immunogenicity in mice and goats. PLoS One 9:e104791CrossRefGoogle Scholar
  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408CrossRefGoogle Scholar
  20. McCormick JB, King IJ, Webb PA, Scribner CL, Craven RB, Johnson KM, Elliott LH, Belmont-Williams R (1986) Lassa fever. Effective therapy with ribavirin. N Engl J Med 314:20–26CrossRefGoogle Scholar
  21. Paeshuyse J, Dallmeier K, Neyts J (2011) Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. Curr Opin Virol 1:590–598CrossRefGoogle Scholar
  22. Pan Q, de Ruiter PE, Metselaar HJ, Kwekkeboom J, de Jonge J, Tilanus HW, Janssen HL, van der Laan LJ (2012a) Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C virus infection in vitro and in vivo. Hepatology 55:1673–1683CrossRefGoogle Scholar
  23. Pan Q, Tilanus HW, Metselaar HJ, Janssen HL, van der Laan LJ (2012b) Virus-drug interactions--molecular insight into immunosuppression and HCV. Nat Rev Gastroenterol Hepatol 9:355–362CrossRefGoogle Scholar
  24. Qu C, Xu L, Yin Y, Peppelenbosch MP, Pan Q, Wang W (2017) Nucleoside analogue 2'-C-methylcytidine inhibits hepatitis E virus replication but antagonizes ribavirin. Arch Virol 162:2989–2996CrossRefGoogle Scholar
  25. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108CrossRefGoogle Scholar
  26. Sen A, Saravanan P, Balamurugan V, Rajak KK, Sudhakar SB, Bhanuprakash V, Parida S, Singh RK (2010) Vaccines against peste des petits ruminants virus. Expert Rev Vaccines 9:785–796CrossRefGoogle Scholar
  27. Thomas E, Ghany MG, Liang TJ (2012) The application and mechanism of action of ribavirin in therapy of hepatitis C. Antivir Chem Chemother 23:1–12CrossRefGoogle Scholar
  28. Wang Z, Bao J, Wu X, Liu Y, Li L, Liu C, Suo L, Xie Z, Zhao W, Zhang W, Yang N, Li J, Wang S, Wang J (2009) Peste des petits ruminants virus in Tibet, China. Emerg Infect Dis 15:299–301CrossRefGoogle Scholar
  29. Wang Y, Metselaar HJ, Peppelenbosch MP, Pan Q (2014a) Chronic hepatitis E in solid-organ transplantation: the key implications of immunosuppressants. Curr Opin Infect Dis 27:303–308CrossRefGoogle Scholar
  30. Wang Y, Zhou X, Debing Y, Chen K, Van Der Laan LJ, Neyts J, Janssen HL, Metselaar HJ, Peppelenbosch MP, Pan Q (2014b) Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology 146:1775–1783CrossRefGoogle Scholar
  31. Wu X, Li L, Li J, Liu C, Wang Q, Bao JY, Zou Y, Ren W, Wang H, Zhang Y, Lv Y, Liu F, Wang S, Ma H, Wang Z (2016) Peste des Petits ruminants viruses re-emerging in China, 2013-2014. Transbound Emerg Dis 63:e441–e446CrossRefGoogle Scholar
  32. Yin Y, Wang Y, Dang W, Xu L, Su J, Zhou X, Wang W, Felczak K, van der Laan LJ, Pankiewicz KW, van der Eijk AA, Bijvelds M, Sprengers D, de Jonge H, Koopmans MP, Metselaar HJ, Peppelenbosch MP, Pan Q (2016) Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. Antivir Res 133:41–49CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Qiu-yan Chang
    • 1
    • 2
  • Fu-cheng Guo
    • 1
  • Xue-rui Li
    • 3
  • Jian-hua Zhou
    • 3
    Email author
  • Xuepeng Cai
    • 3
  • Qiuwei Pan
    • 1
    • 2
  • Xiao-xia Ma
    • 1
    • 2
    • 3
    Email author
  1. 1.Biomedical Research CenterNorthwest Minzu UniversityGansuPeople’s Republic of China
  2. 2.Department of Gastroenterology and HepatologyErasmus MC-University Medical CenterRotterdamThe Netherlands
  3. 3.State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research InstituteChinese Academy of Agricultural SciencesLanzhouPeople’s Republic of China

Personalised recommendations