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.