Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development

Yuebang Yin; Yijin Wang; Wen Dang; Lei Xu; Junhong Su; Xinying Zhou; Wenshi Wang; Krzysztof Felczak; Luc J.W. van der Laan; Krzysztof W. Pankiewicz; Annemiek A. van der Eijk; Marcel Bijvelds; Dave Sprengers; Hugo de Jonge; Marion P.G. Koopmans; Herold J. Metselaar; Maikel P. Peppelenbosch; Qiuwei Pan

doi:10.1016/j.antiviral.2016.07.017

Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development

Yuebang Yin, Yijin Wang, Wen Dang, Lei Xu, Junhong Su, Xinying Zhou, Wenshi Wang, Krzysztof Felczak, Luc J.W. van der Laan, Krzysztof W. Pankiewicz, Annemiek A. van der Eijk, Marcel Bijvelds, Dave Sprengers, Hugo de Jonge, Marion P.G. Koopmans, Herold J. Metselaar, Maikel P. Peppelenbosch, Qiuwei Pan

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 μg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational.

Original language	English (US)
Pages (from-to)	41-49
Number of pages	9
Journal	Antiviral Research
Volume	133
DOIs	https://doi.org/10.1016/j.antiviral.2016.07.017
State	Published - Sep 1 2016

Bibliographical note

Funding Information:
The authors are grateful to Professor Harry Greenberg (Stanford University School of Medicine, USA) for providing the mouse monoclonal antibody against rotavirus VP4 protein. We also thank the general support of the Center for Drug Design (University of Minnesota, USA) for developing the IMPDH inhibitors. This work was supported by the Dutch Digestive Foundation (MLDS) for a career development grant (No. CDG 1304 to Q. P.), the Netherlands Organization for Scientific Research (NWO/ZonMw) for a VENI grant (No. 916-13-032 to Q. P.), the Erasmus MC Mrace grant ( 360525 to Q. P.), and the China Scholarship Council for funding PhD fellowship ( 201307720045 to Y. Y.), ( 201207720007 to Y. W.), ( 201406180072 to W. D.), ( 201306300027 to L. X.), (No. 201206150075 to X. Z), ( 201303250056 to W. W.).

Publisher Copyright:
© 2016 Elsevier B.V.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

Immunosuppressants
Intestinal organoids
Mycophenolic acid
Rotavirus

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Yin, Y., Wang, Y., Dang, W., Xu, L., Su, J., Zhou, X., Wang, W., Felczak, K., van der Laan, L. J. W., Pankiewicz, K. W., van der Eijk, A. A., Bijvelds, M., Sprengers, D., de Jonge, H., Koopmans, M. P. G., Metselaar, H. J., Peppelenbosch, M. P., & Pan, Q. (2016). Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. Antiviral Research, 133, 41-49. https://doi.org/10.1016/j.antiviral.2016.07.017

Yin, Y, Wang, Y, Dang, W, Xu, L, Su, J, Zhou, X, Wang, W, Felczak, K, van der Laan, LJW, Pankiewicz, KW, van der Eijk, AA, Bijvelds, M, Sprengers, D, de Jonge, H, Koopmans, MPG, Metselaar, HJ, Peppelenbosch, MP & Pan, Q 2016, 'Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development', Antiviral Research, vol. 133, pp. 41-49. https://doi.org/10.1016/j.antiviral.2016.07.017

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abstract = "Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 μg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational.",

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author = "Yuebang Yin and Yijin Wang and Wen Dang and Lei Xu and Junhong Su and Xinying Zhou and Wenshi Wang and Krzysztof Felczak and {van der Laan}, {Luc J.W.} and Pankiewicz, {Krzysztof W.} and {van der Eijk}, {Annemiek A.} and Marcel Bijvelds and Dave Sprengers and {de Jonge}, Hugo and Koopmans, {Marion P.G.} and Metselaar, {Herold J.} and Peppelenbosch, {Maikel P.} and Qiuwei Pan",

note = "Funding Information: The authors are grateful to Professor Harry Greenberg (Stanford University School of Medicine, USA) for providing the mouse monoclonal antibody against rotavirus VP4 protein. We also thank the general support of the Center for Drug Design (University of Minnesota, USA) for developing the IMPDH inhibitors. This work was supported by the Dutch Digestive Foundation (MLDS) for a career development grant (No. CDG 1304 to Q. P.), the Netherlands Organization for Scientific Research (NWO/ZonMw) for a VENI grant (No. 916-13-032 to Q. P.), the Erasmus MC Mrace grant ( 360525 to Q. P.), and the China Scholarship Council for funding PhD fellowship ( 201307720045 to Y. Y.), ( 201207720007 to Y. W.), ( 201406180072 to W. D.), ( 201306300027 to L. X.), (No. 201206150075 to X. Z), ( 201303250056 to W. W.). Publisher Copyright: {\textcopyright} 2016 Elsevier B.V. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

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AU - Zhou, Xinying

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AU - Pankiewicz, Krzysztof W.

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Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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