2.3. Ribavirin (Virazole)
It is an open-ring analog of guanosine nucleoside (Figure 3) that was approved by the U.S. FDA in 1985 for the treatment of respiratory syncytial virus [48]. It is also used systemically for chronic hepatitis C virus (HCV) infection [49] and viral hemorrhagic fever [50]. The drug possesses broad-spectrum antiviral activity against both RNA and DNA viruses. To exert its antiviral activity, the drug is to be activated by phosphorylation to generate the triphosphate nucleotide that acts as an inhibitor of RNA synthesis and viral mRNA capping [51]. Other mechanisms have also been proposed to account for its broad spectrum of antiviral activity. Inhibition of host inosine monophosphate dehydrogenase by ribavirin-monophosphate and the resulting depletion of guanosine triphosphate (GTP) pool has been put forward to be another mechanism of action. Decreased intracellular GTP pool decreases viral protein synthesis and limits the replication of viral genome. Ribavirin is also a mutagen that leads to defective virions [52] and it has immunomodulatory actions [53]. Yet, the drug has a U.S. boxed warning pertaining to the risk of hemolytic anemia and potential complications during pregnancy [54].
Ribavirin is currently being evaluated in few trials for the treatment of COVID-19 patients. It is being tested alone (NCT04356677; n = 50) or in combination with nitazoxanide and ivermectin (NCT04392427; n = 100) or with lopinavir/ritonavir and INF β-1b (NCT04276688; n = 127). Recent computational work has shown that ribavirin binds with high affinity to RdRp of SARS-CoV-2 [55]. Furthermore, the MERS-CoV rhesus macaque model revealed promising results for ribavirin and IFN-α 2b [56]. Nevertheless, mixed results came out of treating MERS-CoV infections with a combination of ribavirin and IFNs (IFN-β1 or IFN-α 2a) [57]. Results from the in vitro testing of ribavirin in Vero E6 cells also indicated that the replication and/or the cellular spread of SARS-CoV was not inhibited at concentrations known to inhibit other sensitive viruses [58]. Interestingly, a recent open-label randomized controlled trial (NCT04276688; n = 127) indicated that early triple antiviral therapy of INF-β 1b, ribavirin, and lopinavir/ritonavir was safe and superior to lopinavir/ritonavir alone in alleviating the symptoms and shortening the duration of viral shedding and hospitalization in COVID-19 patients with mild to moderate symptoms [59].