Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays Free

Abstract

The Middle East respiratory syndrome coronavirus (MERS-CoV) presents a novel emerging threat to public health worldwide. Several treatments for infected individuals have been suggested including IFN, ribavirin and passive immunotherapy with convalescent plasma. Administration of IFN-α2b and ribavirin has improved outcomes of MERS-CoV infection in rhesus macaques when administered within 8 h post-challenge. However, detailed and systematic evidence on the activity of other clinically available drugs is limited. Here we compared the susceptibility of MERS-CoV with different IFN products (IFN-α2b, IFN-γ, IFN-universal, IFN-α2a and IFN-β), as well as with two antivirals, ribavirin and mycophenolic acid (MPA), against MERS-CoV (Hu/Jordan-N3/2012) . Of all the IFNs tested, IFN-β showed the strongst inhibition of MERS-CoV , with an IC of 1.37 U ml, 41 times lower than the previously reported IC (56.08 U ml) of IFN-α2b. IFN-β inhibition was confirmed in the virus yield reduction assay, with an IC of 38.8 U ml. Ribavirin did not inhibit viral replication at a dose that would be applicable to current treatment protocols in humans. In contrast, MPA showed strong inhibition, with an IC of 2.87 µM. This drug has not been previously tested against MERS-CoV and may provide an alternative to ribavirin for treatment of MERS-CoV. In conclusion, IFN-β, MPA or a combination of the two may be beneficial in the treatment of MERS-CoV or as a post-exposure intervention in high-risk patients with known exposures to MERS-CoV.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.061911-0
2014-03-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/3/571.html?itemId=/content/journal/jgv/10.1099/vir.0.061911-0&mimeType=html&fmt=ahah

References

  1. Barnard D. L., Day C. W., Bailey K., Heiner M., Montgomery R., Lauridsen L., Winslow S., Hoopes J., Li J. K. other authors 2006; Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin. Antiviral Res 71:53–63 [View Article][PubMed]
    [Google Scholar]
  2. Brown C., Carson G., Chand M., Zambon M. for Public Health England and International Severe Acute Respiratory & Emerging Infection Consortium 2013; Treatment of MERS-CoV: decision support tool. Clinical decision making tool for the treatment of MERS-CoV v.1.1, 29 July 2013. Available at http://isaric.tghn.org/site_media/media/articles/Decision_Support_Document_v1_1_20130729.pdf Accessed 5 October 2013
    [Google Scholar]
  3. Chan J. F., Chan K. H., Kao R. Y., To K. K., Zheng B. J., Li C. P., Li P. T., Dai J., Mok F. K. other authors 2013a; Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 67:606–616 [View Article][PubMed]
    [Google Scholar]
  4. Chan R. W., Chan M. C., Agnihothram S., Chan L. L., Kuok D. I., Fong J. H., Guan Y., Poon L. L., Baric R. S. other authors 2013b; Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures. J Virol 87:6604–6614 [View Article][PubMed]
    [Google Scholar]
  5. de Groot R. J., Baker S. C., Baric R. S., Brown C. S., Drosten C., Enjuanes L., Fouchier R. A., Galiano M., Gorbalenya A. E. other authors 2013; Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol 87:7790–7792 [View Article][PubMed]
    [Google Scholar]
  6. de Wilde A. H., Raj V. S., Oudshoorn D., Bestebroer T. M., van Nieuwkoop S., Limpens R. W., Posthuma C. C., van der Meer Y., Bárcena M. other authors 2013; MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. J Gen Virol 94:1749–1760 [View Article][PubMed]
    [Google Scholar]
  7. Falzarano D., de Wit E., Martellaro C., Callison J., Munster V. J., Feldmann H. 2013a; Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 3:1686[PubMed] [CrossRef]
    [Google Scholar]
  8. Falzarano D., de Wit E., Rasmussen A. L., Feldmann F., Okumura A., Scott D. P., Brining D., Bushmaker T., Martellaro C. other authors 2013b; Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 19:1313–1317 [View Article][PubMed]
    [Google Scholar]
  9. Henry S. D., Metselaar H. J., Lonsdale R. C., Kok A., Haagmans B. L., Tilanus H. W., van der Laan L. J. 2006; Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-α. Gastroenterology 131:1452–1462 [View Article][PubMed]
    [Google Scholar]
  10. ISARIC 2013; Clinical Decision Making Tool for Treatment of MERS-CoV v.1.1 (29 July). International Severe Acute Respiratory & Emerging Infection Consortium (ISARIC). Available at http://isaric.tghn.org/articles/pheisaric-decision-support-document/ Accessed August 5, 2013
    [Google Scholar]
  11. Josset L., Textoris J., Loriod B., Ferraris O., Moules V., Lina B., N’guyen C., Diaz J. J., Rosa-Calatrava M. 2010; Gene expression signature-based screening identifies new broadly effective influenza A antivirals. PLoS ONE 5:e13169 [View Article][PubMed]
    [Google Scholar]
  12. Khan M., Dhanwani R., Patro I. K., Rao P. V., Parida M. M. 2011; Cellular IMPDH enzyme activity is a potential target for the inhibition of Chikungunya virus replication and virus induced apoptosis in cultured mammalian cells. Antiviral Res 89:1–8 [View Article][PubMed]
    [Google Scholar]
  13. Kindler E., Jónsdóttir H. R., Muth D., Hamming O. J., Hartmann R., Rodriguez R., Geffers R., Fouchier R. A., Drosten C. other authors 2013; Efficient replication of the novel human betacoronavirus EMC on primary human epithelium highlights its zoonotic potential. mBio 4:e00611 [View Article][PubMed]
    [Google Scholar]
  14. Leyssen P., Balzarini J., De Clercq E., Neyts J. 2005; The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. J Virol 79:1943–1947 [View Article][PubMed]
    [Google Scholar]
  15. Ludwig S. 2011; Disruption of virus–host cell interactions and cell signaling pathways as an anti-viral approach against influenza virus infections. Biol Chem 392:837–847[PubMed] [CrossRef]
    [Google Scholar]
  16. Morrey J. D., Smee D. F., Sidwell R. W., Tseng C. 2002; Identification of active antiviral compounds against a New York isolate of West Nile virus. Antiviral Res 55:107–116 [View Article][PubMed]
    [Google Scholar]
  17. Pan Q., de Ruiter P. E., Metselaar H. J., Kwekkeboom J., de Jonge J., Tilanus H. W., Janssen H. L., van der Laan L. J. 2012; Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C virus infection in vitro and in vivo. Hepatology 55:1673–1683 [View Article][PubMed]
    [Google Scholar]
  18. Reed L. J., Muench H. 1938; A simple method of estimating fifty per cent endpoints. Am J Epidemiol 27:493–497
    [Google Scholar]
  19. Smee D. F., Bray M., Huggins J. W. 2001; Antiviral activity and mode of action studies of ribavirin and mycophenolic acid against orthopoxviruses in vitro. Antivir Chem Chemother 12:327–335[PubMed] [CrossRef]
    [Google Scholar]
  20. Tisoncik J. R., Simmons C. P., Farrar J., Martin T. R., Katze M. G. 2012; Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76:16–32 [View Article][PubMed]
    [Google Scholar]
  21. World Health Organization 2013; Global Alert and Response (GAR). Middle East respiratory syndrome coronavirus (MERS-CoV) – update. Available http://www.who.int/csr/don/2013_09_20/en/ Accessed 5 October 2013
    [Google Scholar]
  22. Zaki A. M., Van Boheemen S., Bestebroer T. M., Osterhaus A. D. M. E., Fouchier R. A. M. 2012; Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367:1814–1820 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.061911-0
Loading
/content/journal/jgv/10.1099/vir.0.061911-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed