Nucleoside Analogs
Nucleoside analogs can interfere with cellular nucleotide synthesis pathways and terminate viral genome replication through accumulating mutations and cutting off the entry of natural nucleotides (Wang et al., 2016). Since nucleosides and nucleotides are the basic components of viral nucleic acids, nucleoside analogs serve as viral RNA synthesis inhibitors in a wide spectrum of RNA viruses. With the view of the targeting ability toward RdRp, nucleoside analogs are responsible for viral RNA replication (Debing et al., 2014).
Ribavirin is a guanine analog among approved nucleoside analogs used to treat hepatitis c virus and respiratory syncytial virus infections and has been harnessed to cure patients with SARS (So et al., 2003). Ribavirin was extensively leveraged for patients with or without concomitant usage of steroids during the SARS outbreak in 2003 (Wenzel and Edmond, 2003). When combined with IFN-β, it can exert the synergistical inhibition effect on SARS-associated coronavirus replication in vitro (Morgenstern et al., 2005). However, the efficacy and safety of this agent remain uncertain, and it may arouse adverse reactions like anemia in high doses (Al-Tawfiq et al., 2014). In COVID-19 therapy, ribavirin was utilized with pegylated interferon for stimulating the innate antiviral reaction at a relatively lower dose to curtail side effects.
In addition, another promising guanine analog is favipiravir (T-705), which has been approved in Japan for the therapy of influenza virus infections and has also been demonstrated to suppress the replication of Ebola, yellow fever, enterovirus, and norovirus (De Clercq, 2019). Recently, Wang and coworkers suggested that favipiravir may also be a potential candidate for COVID-19 therapy, which showed effective antiviral activity in Vero E6 cells with an EC50 value of around 61 μM. To improve the condition of COVID-19 patients, favipiravir was utilized with other antiviral drugs like baloxavir marboxil (Wang et al., 2020b).
As an adenine analogue with a similar chemical structure to the approved HIV reverse transcriptase inhibitor tenofovir alafenamide, remdesivir (GS-5734) exhibits broad-spectrum antiviral activity against several RNA viruses and has the capacity of competing with RdRp (Tchesnokov et al., 2019). It also possesses outstanding in vitro antiviral activity compared with lopinavir and ritonavir (Sheahan et al., 2020). In the United States, the first case of SARS-CoV-2 infection was reported, and remdesivir was administered. The patient’s clinical condition improved after only one day of remdesivir treatment (Holshue et al., 2020). A newly released research offered remdesivir for COVID-19 inpatients on the basis of sympathy. In the cohort of patients admitted for treatment of severe COVID-19, patients treated with sympathetic remdesivir achieved relatively good clinical improvement (36 of 53 patients (68%)) (Grein et al., 2020). However, recently, leaked data from a crucial remdesivir investigation suggests this potent coronavirus agent may not be effective. Although the chief medical officer of Gilead Sciences said that the summary post online might include inappropriate characterizations of the study and the study was terminated early due to low enrollment (Park, 2020). The real anti-SARS-CoV-2 activity of remdesivir need to be further studied in the near future.