Citation: Hongbo Guo, Dan Liu, Kuan Liu, Yao Hou, Chunyang Li, Qiudi Li, Xiaohui Ding, Monique M. A. Verstegen, Jikai Zhang, Lingli Wang, Yibo Ding, Renxian Tang, Xiucheng Pan, Kuiyang Zheng, Luc J. W. van der Laan, Qiuwei Pan, Wenshi Wang. Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions .VIROLOGICA SINICA, 2024, 39(1) : 123-133.  http://dx.doi.org/10.1016/j.virs.2023.11.006

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

  • Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

  • 加载中
  • 10.1016j.virs.2023.11.006-ESM.docx
    1. Aithal, G.P., 2011. Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol, 7, 139-150.

    2. Cha, Y., Erez, T., Reynolds, I.J., Kumar, D., Ross, J., Koytiger, G., Kusko, R., Zeskind, B., Risso, S., Kagan, E., Papapetropoulos, S., Grossman, I.,Laifenfeld, D., 2018. Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol, 175, 168-180.

    3. Chen, S., Ding, S., Yin, Y., Xu, L., Li, P., Peppelenbosch, M.P., Pan, Q.,Wang, W., 2019. Suppression of pyrimidine biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. Antiviral Res, 167, 35-44.

    4. Debing, Y., Gisa, A., Dallmeier, K., Pischke, S., Bremer, B., Manns, M., Wedemeyer, H., Suneetha, P.V.,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, 1008-1011 e1007; quiz e1015-1006.

    5. Debing, Y., Ramiere, C., Dallmeier, K., Piorkowski, G., Trabaud, M.A., Lebosse, F., Scholtes, C., Roche, M., Legras-Lachuer, C., De Lamballerie, X., Andre, P.,Neyts, J., 2016. Hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity. J Hepatol, 65, 499-508.

    6. Del Bello, A., Guilbeau-Frugier, C., Josse, A.G., Rostaing, L., Izopet, J.,Kamar, N., 2015. Successful treatment of hepatitis E virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin. Transpl Infect Dis, 17, 279-283.

    7. Desai, A.N., Mohareb, A.M., Elkarsany, M.M., Desalegn, H., Madoff, L.C.,Lassmann, B., 2022. Viral Hepatitis E Outbreaks in Refugees and Internally Displaced Populations, sub-Saharan Africa, 2010-2020. Emerg Infect Dis, 28, 1074-1076.

    8. Dhillon, S., 2021. Lonafarnib: First Approval. Drugs, 81, 283-289.

    9. Dwek, R.A., Bell, J.I., Feldmann, M.,Zitzmann, N., 2022. Host-targeting oral antiviral drugs to prevent pandemics. Lancet, 399, 1381-1382.

    10. European Association for the Study of the Liver. Electronic Address, E.E.E.,European Association for the Study of The, L., 2018. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol, 68, 1256-1271.

    11. Fox, R.J., Wiendl, H., Wolf, C., De Stefano, N., Sellner, J., Gryb, V., Rejdak, K., Bozhinov, P.S., Tomakh, N., Skrypchenko, I.,Muehler, A.R., 2022. A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis. Ann Clin Transl Neurol, 9, 977-987.

    12. Guinault, D., Ribes, D., Delas, A., Milongo, D., Abravanel, F., Puissant-Lubrano, B., Izopet, J.,Kamar, N., 2016. Hepatitis E Virus-Induced Cryoglobulinemic Glomerulonephritis in a Nonimmunocompromised Person. Am J Kidney Dis, 67, 660-663.

    13. Hooda, P., Chaudhary, M., Parvez, M.K., Sinha, N.,Sehgal, D., 2022. Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase. Viruses, 14.

    14. Ianevski, A., Giri, A.K.,Aittokallio, T., 2022. SynergyFinder 3.0: an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples. Nucleic Acids Res, 50, W739-W743.

    15. Jones, S.W., Penman, S.L., French, N.S., Park, B.K.,Chadwick, A.E., 2021. Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models. Toxicol In Vitro, 72, 105096.

    16. Kamar, N., Abravanel, F., Lhomme, S., Rostaing, L.,Izopet, J., 2015. Hepatitis E virus: chronic infection, extra-hepatic manifestations, and treatment. Clin Res Hepatol Gastroenterol, 39, 20-27.

    17. Kamar, N., Del Bello, A., Abravanel, F., Pan, Q.,Izopet, J., 2022. Unmet Needs for the Treatment of Chronic Hepatitis E Virus Infection in Immunocompromised Patients. Viruses, 14.

    18. Kamar, N., Izopet, J., Tripon, S., Bismuth, M., Hillaire, S., Dumortier, J., Radenne, S., Coilly, A., Garrigue, V., D'alteroche, L., Buchler, M., Couzi, L., Lebray, P., Dharancy, S., Minello, A., Hourmant, M., Roque-Afonso, A.M., Abravanel, F., Pol, S., Rostaing, L.,Mallet, V., 2014. Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med, 370, 1111-1120.

    19. Kamar, N., Marion, O., Abravanel, F., Izopet, J.,Dalton, H.R., 2016. Extrahepatic manifestations of hepatitis E virus. Liver Int, 36, 467-472.

    20. Karki, P., Malik, S., Mallick, B., Sharma, V.,Rana, S.S., 2016. Massive Hemolysis Causing Renal Failure in Acute Hepatitis E Infection. J Clin Transl Hepatol, 4, 345-347.

    21. Kaushik, N., Subramani, C., Anang, S., Muthumohan, R., Shalimar, Nayak, B., Ranjith-Kumar, C.T.,Surjit, M., 2017. Zinc Salts Block Hepatitis E Virus Replication by Inhibiting the Activity of Viral RNA-Dependent RNA Polymerase. J Virol, 91.

    22. Kinast, V., Burkard, T.L., Todt, D.,Steinmann, E., 2019. Hepatitis E Virus Drug Development. Viruses, 11.

    23. Kitrinos, K.M., Corsa, A., Liu, Y., Flaherty, J., Snow-Lampart, A., Marcellin, P., Borroto-Esoda, K.,Miller, M.D., 2014. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology, 59, 434-442.

    24. Li, P., Li, Y., Wang, Y., Liu, J., Lavrijsen, M., Li, Y., Zhang, R., Verstegen, M.M.A., Wang, Y., Li, T.C., Ma, Z., Kainov, D.E., Bruno, M.J., De Man, R.A., Van Der Laan, L.J.W., Peppelenbosch, M.P.,Pan, Q., 2022. Recapitulating hepatitis E virus-host interactions and facilitating antiviral drug discovery in human liver-derived organoids. Sci Adv, 8, eabj5908.

    25. Li, P., Liu, J., Li, Y., Su, J., Ma, Z., Bramer, W.M., Cao, W., De Man, R.A., Peppelenbosch, M.P.,Pan, Q., 2020. The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis. Liver Int, 40, 1516-1528.

    26. Luthra, P., Naidoo, J., Pietzsch, C.A., De, S., Khadka, S., Anantpadma, M., Williams, C.G., Edwards, M.R., Davey, R.A., Bukreyev, A., Ready, J.M.,Basler, C.F., 2018. Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. Antiviral Res, 158, 288-302.

    27. Mcbride, J.T., 1985. Ribavirin and RSV: a new approach to an old disease. Pediatr Pulmonol, 1, 294-295.

    28. Muehler, A., Kohlhof, H., Groeppel, M.,Vitt, D., 2020a. Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU-838) After Single and Multiple Ascending Oral Doses in Healthy Male Subjects. Eur J Drug Metab Pharmacokinet, 45, 557-573.

    29. Muehler, A., Peelen, E., Kohlhof, H., Groppel, M.,Vitt, D., 2020b. Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord, 43, 102129.

    30. Netzler, N.E., Enosi Tuipulotu, D., Vasudevan, S.G., Mackenzie, J.M.,White, P.A., 2019. Antiviral Candidates for Treating Hepatitis E Virus Infection. Antimicrob Agents Chemother, 63.

    31. Pedroni, L., Dellafiora, L., Varra, M.O., Galaverna, G.,Ghidini, S., 2022. In silico study on the Hepatitis E virus RNA Helicase and its inhibition by silvestrol, rocaglamide and other flavagline compounds. Sci Rep, 12, 15512.

    32. Pischke, S., Hartl, J., Pas, S.D., Lohse, A.W., Jacobs, B.C.,Van Der Eijk, A.A., 2017. Hepatitis E virus: Infection beyond the liver? J Hepatol, 66, 1082-1095.

    33. Qu, C., Xu, L., Yin, Y., Peppelenbosch, M.P., Pan, Q.,Wang, W., 2017. Nucleoside analogue 2'-C-methylcytidine inhibits hepatitis E virus replication but antagonizes ribavirin. Arch Virol, 162, 2989-2996.

    34. Roessler, H.I., Knoers, N., Van Haelst, M.M.,Van Haaften, G., 2021. Drug Repurposing for Rare Diseases. Trends Pharmacol Sci, 42, 255-267.

    35. Shukla, P., Nguyen, H.T., Faulk, K., Mather, K., Torian, U., Engle, R.E.,Emerson, S.U., 2012. Adaptation of a genotype 3 hepatitis E virus to efficient growth in cell culture depends on an inserted human gene segment acquired by recombination. J Virol, 86, 5697-5707.

    36. Therapeutics, P.-I., https://imux.com/pipeline/.

    37. U.S. Fda, 2010. FDA Drug Safety Communication: New boxed warning for severe liver injury with arthritis drug Arava (leflunomide). www.fda.gov/drugs. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-new-boxed-warning-severe-liver-injury-arthritis-drug-arava-leflunomide

    38. U.S. Fda, 2012. FDA Approved Labeling Text - NDA 20292. www.fda.gov/drugs. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdfVehreschild, M., Atanasov, P., Yurko, K., Oancea, C., Popov, G., Smesnoi, V., Placinta, G., Kohlhof, H., Vitt, D., Peelen, E., Mihajlovic, J.,Muehler, A.R., 2022. Safety and Efficacy of Vidofludimus Calcium in Patients Hospitalized with COVID-19: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial. Infect Dis Ther, 11, 2159-2176.

    39. Velavan, T.P., Pallerla, S.R., Johne, R., Todt, D., Steinmann, E., Schemmerer, M., Wenzel, J.J., Hofmann, J., Shih, J.W.K., Wedemeyer, H.,Bock, C.T., 2021. Hepatitis E: An update on One Health and clinical medicine. Liver Int, 41, 1462-1473.

    40. Wagoner, J., Herring, S., Hsiang, T.Y., Ianevski, A., Biering, S.B., Xu, S., Hoffmann, M., Pohlmann, S., Gale, M., Jr., Aittokallio, T., Schiffer, J.T., White, J.M.,Polyak, S.J., 2022. Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2. Microbiol Spectr, 10, e0333122.

    41. Wang, B., Mahsoub, H.M., Li, W., Heffron, C.L., Tian, D., Hassebroek, A.M., Leroith, T.,Meng, X.J., 2023. Ribavirin Treatment Failure-Associated Mutation, Y1320H, in the RNA-Dependent RNA Polymerase of Genotype 3 Hepatitis E Virus (HEV) Enhances Virus Replication in a Rabbit HEV Infection Model. mBio, 14, e0337222.

    42. Wang, Y., Wang, W., Xu, L., Zhou, X., Shokrollahi, E., Felczak, K., Van Der Laan, L.J., Pankiewicz, K.W., Sprengers, D., Raat, N.J., Metselaar, H.J., Peppelenbosch, M.P.,Pan, Q., 2016. Cross Talk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication. Antimicrob Agents Chemother, 60, 2834-2848.

    43. Wang, W., Cui, J., Ma, H., Lu, W., Huang, J. 2021. Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine. Frontiers in Oncol, 11, 684961.

    44. Webb, G.W.,Dalton, H.R., 2019. Hepatitis E: an underestimated emerging threat. Ther Adv Infect Dis, 6, 2049936119837162.

    45. Xiong, R., Zhang, L., Li, S., Sun, Y., Ding, M., Wang, Y., Zhao, Y., Wu, Y., Shang, W., Jiang, X., Shan, J., Shen, Z., Tong, Y., Xu, L., Chen, Y., Liu, Y., Zou, G., Lavillete, D., Zhao, Z., Wang, R., Zhu, L., Xiao, G., Lan, K., Li, H.,Xu, K., 2020. Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein Cell, 11, 723-739.

  • 加载中

Article Metrics

Article views(2824) PDF downloads(16) Cited by()

Related
Proportional views

    Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

      Corresponding author: Hongbo Guo, hongbo.guo@xzhmu.edu.cn
      Corresponding author: Qiuwei Pan, q.pan@erasmusmc.nl
      Corresponding author: Wenshi Wang, wenshi.wang@xzhmu.edu.cn
    • a. Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, China;
    • b. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NL-3015 CN, the Netherlands;
    • c. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, 3015CE, NL-3015 CN, the Netherlands;
    • d. Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Abstract: Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

    Reference (45) Relative (20)

    目录

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return