ArticleAntimicrobial agents and chemotherapy2017
Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication.
Article in Antimicrobial agents and chemotherapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Article
- Virus-Host Protein Interaction Network of the Hepatitis E Virus ORF2-4 by Mammalian Two-Hybrid Assays.Viruses · 2023Article
- Voclosporin and the Antiviral Effect Against SARS-CoV-2 in Immunocompromised Kidney Patients.Kidney international reports · 2023Article
- Growth Transformation of B Cells by Epstein-Barr Virus RequiresMicrobiology spectrum · 2023Article
- Inhibitors of Nucleotide Biosynthesis as Candidates for a Wide Spectrum of Antiviral Chemotherapy.Microorganisms · 2022Review
- SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome.eLife · 2022Article
- The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.Transplant international : official journal of the European Society for Organ Transplantation · 2022Article
- SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling.Frontiers in immunology · 2022Article
- SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation.bioRxiv : the preprint server for biology · 2021Article
- Strategy, Progress, and Challenges of Drug Repurposing for Efficient Antiviral Discovery.Frontiers in pharmacology · 2021Review
- 2'-Fluoro-2'-deoxycytidine inhibits murine norovirus replication and synergizes MPA, ribavirin and T705.Archives of virology · 2020Article
- The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19.Journal of autoimmunity · 2020Review
- Antiviral activity of ribavirin and favipiravir against human astroviruses.Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology · 2020Article
- IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways.Journal of experimental & clinical cancer research : CR · 2018Article
- The IMPDH inhibitors, ribavirin and mycophenolic acid, inhibit peste des petits ruminants virus infection.Veterinary research communications · 2018Article
- Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response.Antimicrobial agents and chemotherapy · 2018Article
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concentration, therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.
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