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

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-a2b 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-a2b, IFN-c, IFN-universal, IFN-a2a and IFN-b), 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-b showed the strongst inhibition of MERS-CoV in vitro, with an IC 50 of 1.37 U ml "1 , 41 times lower than the previously reported IC 50 (56.08 U ml "1 ) of IFN-a2b. IFN-b inhibition was confirmed in the virus yield reduction assay, with an IC 90 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 IC 50 of 2.87 mM. 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-b, 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.

The emergence of the Middle East Respiratory Syndrome coronavirus

“…For instance, MERS‐CoV lacks a homologue of the SARS‐CoV ORF6 protein, which blocks the STAT1‐activating effects of IFNs and ultimately the transcriptional activation of downstream antiviral genes (Wilde et al ., ). A comparison of five different IFNs has shown IFN‐β to be the most potent inhibitor of MERS‐CoV (Hart et al ., ). Although high concentrations of ribavirin were effective in vitro in one study (Falzarano et al .,), another study found no inhibitory effects of ribavirin at a dose translatable to current drug regiments in humans (Hart et al ., ).…”

Middle East Respiratory Syndrome

“…Mycophenolic acid has broad antiviral activity, but its mechanism of action is not clearly understood. It may have both direct and indirect antiviral activity through the modulation of INF response activities, and it has been shown to have a solitary or synergistic effect with INF on MERS-CoV replication in vitro (52).…”

What are our pharmacotherapeutic options for MERS-CoV?

“…In vitro studies also showed that the addition of IFN-b had a significant antiviral effect on MERS-CoV resulting in a 3-log reduction of the virus to undetectable levels [28]. In another study comparing the susceptibility of MERS-CoV with different interferon products (IFN-a2b, IFN-g, IFN-universal and IFN-a2a, IFN-b), IFN-b had the strongest inhibition of MERS-CoV in vitro [29]. Pegylated IFN-a was 50-to 100-times more effective in vitro for MERS-CoV than SARSCoV [3].…”

“…In vitro studies showed that mycophenolic acid had low concentration required for 50% inhibition of enzyme activity and high selectivity index [11]. Mycophenolic acid showed strong inhibition of MERS-CoV in vitro [12]. Cyclosporine A inhibits cyclophilins by blocking the replication of all coronavirus genera, including SARS-CoV [13].…”