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

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) in vitro. Of all the IFNs tested, IFN-β showed the strongst inhibition of MERS-CoV in vitro, with an IC₅₀ of 1.37 U ml(-1), 41 times lower than the previously reported IC₅₀ (56.08 U ml(-1)) of IFN-α2b. IFN-β inhibition was confirmed in the virus yield reduction assay, with an IC90 of 38.8 U ml(-1). Ribavirin did not inhibit viral replication in vitro at a dose that would be applicable to current treatment protocols in humans. In contrast, MPA showed strong inhibition, with an IC₅₀ 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.

[1]  U. Emirates b Middle East respiratory syndrome coronavirus (MERS-CoV): update , 2014 .

[2]  K. To,et al.  Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus , 2013, Journal of Infection.

[3]  M. Katze,et al.  Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques , 2013, Nature Medicine.

[4]  T. Bestebroer,et al.  MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment , 2013, The Journal of general virology.

[5]  Christian Drosten,et al.  Commentary: Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group , 2013, Journal of Virology.

[6]  H. Feldmann,et al.  Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin , 2013, Scientific Reports.

[7]  Y. Guan,et al.  Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures , 2013, Journal of Virology.

[8]  R. Geffers,et al.  Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential , 2013, mBio.

[9]  A. Osterhaus,et al.  Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. , 2012, The New England journal of medicine.

[10]  J. Kwekkeboom,et al.  Mycophenolic acid augments interferon‐stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo , 2012, Hepatology.

[11]  Michael G. Katze,et al.  Into the Eye of the Cytokine Storm , 2012, Microbiology and Molecular Reviews.

[12]  Stephan Ludwig,et al.  Disruption of virus-host cell interactions and cell signaling pathways as an anti-viral approach against influenza virus infections , 2011, Biological chemistry.

[13]  M. Parida,et al.  Cellular IMPDH enzyme activity is a potential target for the inhibition of Chikungunya virus replication and virus induced apoptosis in cultured mammalian cells. , 2011, Antiviral research.

[14]  B. Loriod,et al.  Gene Expression Signature-Based Screening Identifies New Broadly Effective Influenza A Antivirals , 2010, PloS one.

[15]  B. Haagmans,et al.  Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-alpha. , 2006, Gastroenterology.

[16]  Jongdae Lee,et al.  Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin , 2006, Antiviral Research.

[17]  E. De Clercq,et al.  The Predominant Mechanism by Which Ribavirin Exerts Its Antiviral Activity In Vitro against Flaviviruses and Paramyxoviruses Is Mediated by Inhibition of IMP Dehydrogenase , 2005, Journal of Virology.

[18]  D. Smee,et al.  Identification of active antiviral compounds against a New York isolate of West Nile virus. , 2002, Antiviral research.

[19]  D. Smee,et al.  Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro , 2001, Antiviral chemistry & chemotherapy.

[20]  L. Reed,et al.  A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT ENDPOINTS , 1938 .