3.3  CoV replication inhibitors
Similar to developing vaccines, drugs effective against other RNA viruses were also repurposed for CoVs. Two major types of drugs being nucleoside analogues and immunomodulators. So far, the most common therapies tried in patients with CoVs are ribavirin, lopinavir/ritonavir, IFN, or their combinations [74]. Despite the antiviral activity observed with in vitro studies, the clinical effect was not consistent [75], in that ribavirin does not prolong the survival of SARS-CoV patients [74,76], while lopinavir/ritonavir plus ribavirin seemed to improve clinical outcomes for SARS patients [77], but the improvement was not confirmed in MERS-CoV patients. IFNs showed effective at inducing antiviral activity against both SARS-CoV and MRES-CoV, but without significant improvement in the outcomes for the patients [78,79]. In addition to the drug regimens used in patients, numerous drugs developed for the treatment of infection with CoVs were thoroughly discussed in the literature [57].
However, replication of an RNA virus usually generates progeny viruses with a highly diverse genome. Recombination also easily takes place between viral genomes [80], and these gene level changes may result in drug resistance if the mutations affect the drug target domain. Development of drugs is also hampered by various evaluation methods and animal models used for testing drug activity among different labs worldwide, which could postpone selection of the best drug for clinical trials.