Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative representative of a severe respiratory illness resulted in widespread human infections and deaths in nearly all of the countries since late 2019. There is no therapeutic FDA-approved drug against SARS-CoV-2 infection, although a combination of anti-viral drugs is directly being practiced in some countries. A broad-spectrum of antiviral agents are being currently evaluated in clinical trials, and in this review, we specifically focus on the application of Remdesivir (RVD) as a potential anti-viral compound against Middle East respiratory syndrome (MERS) -CoV, SARS-CoV and SARS-CoV-2. First, we overview the general information about SARS-CoV-2, followed by application of RDV as a nucleotide analogue which can potentially inhibits RNA-dependent RNA polymerase of COVs. Afterwards, we discussed the kinetics of SARS- or MERS-CoV proliferation in animal models which is significantly different compared to that in humans. Finally, some ongoing challenges and future perspective on the application of RDV either alone or in combination with other anti-viral agents against CoVs infection were surveyed to determine the efficiency of RDV in preclinical trials. As a result, this paper provides crucial evidence of the potency of RDV to prevent SARS-CoV-2 infections.Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; Corona virus; MERS; SARS; SARS-CoV-2; anti-viral; remdesivir.

Figure 1.

Some specifications such as origin, transmission and clinical symptoms of SARS-CoV-2. Reprinted with permission from Ref. (Guo et al., 2020).

Figure 2.

(A) ExoN (-) virus are more sensitive to anti-viral drug. (i) Viral titer of WT and ExoN (-) viruses, (ii) percentage of viral titer reduction. (B) The effect of different variations on the viral titer value. (i) The SARS-CoV titer against different concentrations of GS-5734 over time, (ii) The MERS-CoV titer against different concentrations of GS-5734 over time. Reprinted with permission from Ref. (Agostini et al., 2018).

Figure 3.

Anti-viral test. (i) HCoV-OC43 anti-viral assay plate layout in human hepatoma (Huh7) cells incubated with different agents, (ii) A decrease in viral foci assayed by antibody staining, (iii) percentage of inhibition, (iv) dose response of RDV, (v) the number of spots per well (A, B, C), (vi) EC₅₀ values. Reprinted with permission form Ref. (Brown et al., 2019).

Figure 4.

Percentage of inhibition of MERS-CoV replication as well as cytotoxicity stimulated by different anti-viral agents in vitro. The Figure was reprinted with permission from Ref. (Sheahan et al., 2020).