MERS-coronavirus: From discovery to intervention

Widagdo, W.; Okba, Nisreen M.A.; Stalin Raj, V.; Haagmans, Bart L.

Several studies are dedicated to the development of effective treatments against MERS-CoV, either based on the use of broad-spectrum or MERS-CoV specific therapeutic agents. In-vitro, MERS-CoV is highly sensitive to type I interferon (IFN). While MERS-CoV replication in Vero cells could be efficiently reduced with low levels of recombinant IFNα, in the case of SARS-CoV much higher concentrations are needed to achieve a similar inhibition of viral replication [18] . Other broad spectrum antivirals, such as ribavirin, mycophenolic acid and cyclosporine-A, also have antiviral activity against MERS-CoV in-vitro. Combinations of ribavirin and IFNα may have a synergistic effect as shown by invitro and in vivo studies in rhesus macaques [19, 20] . However, treatment should be initiated quite early after the infection; hence it has a limited effective therapeutic window of opportunity. Experimental SARS-CoV infection in mice showed that administration of type I IFN 6 h post inoculation (pi) is life-saving, while 24 h pi it is detrimental, supporting the limited effective therapeutic window of opportunity [21] . The importance of having sufficient type I IFN being produced early after the SARS-CoV infection has also been investigated in experimentally infected macaques. Advanced-age macaques do not mount sufficient type I IFN responses upon SARS-CoV inoculation but instead upregulate expression of interleukin-8 (IL-8), a neutrophil chemoattractant, leading to the development of acute lung injury (ALI). Most importantly, treatment with type I IFN at day 1 and 3 pi prevents this IL-8 mediated ALI [22] . The limited effective therapeutic window of opportunity of type I IFN might explain why a cocktail regimen of ribavirin and IFNα did not improve the overall survival rates seen in human MERS cases, despite these promising in-vitro and in-vivo results [18] [19] [20] 23, 24] . Other candidate drugs were identified by screening for MERS-CoV inhibitory activity using FDA-approved drugs that are used to treat other diseases. Two research groups reported that both chloroquine and chlorpromazine have potential therapeutic antiviral activity. Chlorpromazine affects the assembly of clathrin-coated pits at the plasma membrane, while chloroquine plays a role in endosomal acidification. By interrupting these biological processes, those drugs likely inhibit MERS-CoV endocytosis at the host cell membrane and fusion in endosomes intracellularly [25, 26] .