Antiviral Drugs
Several classes of routinely used antiviral drugs, like oseltamivir (neuraminidase inhibitor), acyclovir, ganciclovir, and ribavirin, do not have any effect on COVID-19 and, hence, are not recommended (187). Oseltamivir, a neuraminidase inhibitor, has been explored in Chinese hospitals for treating suspected COVID-19 cases, although proven efficacy against SARS-CoV-2 is still lacking for this drug (7). The in vitro antiviral potential of FAD-approved drugs, viz., ribavirin, penciclovir, nitazoxanide, nafamostat, and chloroquine, tested in comparison to remdesivir and favipiravir (broad-spectrum antiviral drugs) revealed remdesivir and chloroquine to be highly effective against SARS-CoV-2 infection in vitro (194). Ribavirin, penciclovir, and favipiravir might not possess noteworthy in vivo antiviral actions for SARS-CoV-2, since higher concentrations of these nucleoside analogs are needed in vitro to lessen the viral infection. Both remdesivir and chloroquine are being used in humans to treat other diseases, and such safer drugs can be explored for assessing their effectiveness in COVID-19 patients.
Several therapeutic agents, such as lopinavir/ritonavir, chloroquine, and hydroxychloroquine, have been proposed for the clinical management of COVID-19 (299). A molecular docking study, conducted in the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using different commercially available antipolymerase drugs, identified that drugs such as ribavirin, remdesivir, galidesivir, tenofovir, and sofosbuvir bind RdRp tightly, indicating their vast potential to be used against COVID-19 (305). A broad-spectrum antiviral drug that was developed in the United States, tilorone dihydrochloride (tilorone), was previously found to possess potent antiviral activity against MERS, Marburg, Ebola, and Chikungunya viruses (306). Even though it had broad-spectrum activity, it was neglected for an extended period. Tilorone is another antiviral drug that might have activity against SARS-CoV-2.
Remdesivir, a novel nucleotide analog prodrug, was developed for treating Ebola virus disease (EVD), and it was also found to inhibit the replication of SARS-CoV and MERS-CoV in primary human airway epithelial cell culture systems (195). Recently, in vitro study has proven that remdesivir has better antiviral activity than lopinavir and ritonavir. Further, in vivo studies conducted in mice also identified that treatment with remdesivir improved pulmonary function and reduced viral loads and lung pathology both in prophylactic and therapeutic regimens compared to lopinavir/ritonavir-IFN-γ treatment in MERS-CoV infection (8). Remdesivir also inhibits a diverse range of coronaviruses, including circulating human CoV, zoonotic bat CoV, and prepandemic zoonotic CoV (195). Remdesivir is also considered the only therapeutic drug that significantly reduces pulmonary pathology (8). All these findings indicate that remdesivir has to be further evaluated for its efficacy in the treatment of COVID-19 infection in humans. The broad-spectrum activity exhibited by remdesivir will help control the spread of disease in the event of a new coronavirus outbreak.
Chloroquine is an antimalarial drug known to possess antiviral activity due to its ability to block virus-cell fusion by raising the endosomal pH necessary for fusion. It also interferes with virus-receptor binding by interfering with the terminal glycosylation of SARS-CoV cellular receptors, such as ACE2 (196). In a recent multicenter clinical trial that was conducted in China, chloroquine phosphate was found to exhibit both efficacy and safety in the therapeutic management of SARS-CoV-2-associated pneumonia (197). This drug is already included in the treatment guidelines issued by the National Health Commission of the People’s Republic of China. The preliminary clinical trials using hydroxychloroquine, another aminoquinoline drug, gave promising results. The COVID-19 patients received 600 mg of hydroxychloroquine daily along with azithromycin as a single-arm protocol. This protocol was found to be associated with a noteworthy reduction in viral load. Finally, it resulted in a complete cure (271); however, the study comprised a small population and, hence, the possibility of misinterpretation could arise. However, in another case study, the authors raised concerns over the efficacy of hydroxychloroquine-azithromycin in the treatment of COVID-19 patients, since no observable effect was seen when they were used. In some cases, the treatment was discontinued due to the prolongation of the QT interval (307). Hence, further randomized clinical trials are required before concluding this matter.
Recently, another FDA-approved drug, ivermectin, was reported to inhibit the in vitro replication of SARS-CoV-2. The findings from this study indicate that a single treatment of this drug was able to induce an ∼5,000-fold reduction in the viral RNA at 48 h in cell culture. (308). One of the main disadvantages that limit the clinical utility of ivermectin is its potential to cause cytotoxicity. However, altering the vehicles used in the formulations, the pharmacokinetic properties can be modified, thereby having significant control over the systemic concentration of ivermectin (338). Based on the pharmacokinetic simulation, it was also found that ivermectin may have limited therapeutic utility in managing COVID-19, since the inhibitory concentration that has to be achieved for effective anti-SARS-CoV-2 activity is far higher than the maximum plasma concentration achieved by administering the approved dose (340). However, ivermectin, being a host-directed agent, exhibits antiviral activity by targeting a critical cellular process of the mammalian cell. Therefore, the administration of ivermectin, even at lower doses, will reduce the viral load at a minor level. This slight decrease will provide a great advantage to the immune system for mounting a large-scale antiviral response against SARS-CoV-2 (341). Further, a combination of ivermectin and hydroxychloroquine might have a synergistic effect, since ivermectin reduces viral replication, while hydroxychloroquine inhibits the entry of the virus in the host cell (339). Further, in vivo studies and randomized clinical control trials are required to understand the mechanism as well as the clinical utility of this promising drug.
Nafamostat is a potent inhibitor of MERS-CoV that acts by preventing membrane fusion. Nevertheless, it does not have any sort of inhibitory action against SARS-CoV-2 infection (194). Recently, several newly synthesized halogenated triazole compounds were evaluated, using fluorescence resonance energy transfer (FRET)-based helicase assays, for their ability to inhibit helicase activity.
Among the evaluated compounds, 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-iodophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol were found to be the most potent. These compounds were used for in silico studies, and molecular docking was accomplished into the active binding site of MERS-CoV helicase nsp13 (21). Further studies are required for evaluating the therapeutic potential of these newly identified compounds in the management of COVID-19 infection.