3.1. RNA dependent RNA polymerase (RdRp)
SARS-CoV-2 is an RNA virus and its replication is dependent on RdRp. Besides its 4 structural proteins, SARS-CoV-2 has 16 non-structural proteins (NSPs). NSP12 is one of the conserved NSPs among coronaviruses and is a vital enzyme that functions as an RdRp (Perlman & Netland, 2009; Wu et al., 2020b). In addition, NSP8 functions as a primase that is associated with RNA synthesis (Perlman & Netland, 2009). NSP8 interacts with NSP7 for their primer dependent RdRp activity. The presence of NSP7 and NSP8 is necessary for the binding activity of NSP12 to the template-primer RNA (Yin et al., 2020).
Since there are 96.35%, 98.8% and 97.5% similarities in NSP12, NSP7 and NSP8 between SARS-CoV and SARS-CoV-2, respectively (Ruan, Yang, Wang, Jiang & Song, 2020), inhibitors of the NSP12–NSP7–NSP8 complex for SARS-CoV may also inhibit the complex of SARS-CoV-2 (Yin et al., 2020). Therefore, the NSP12–NSP7–NSP8 complex and RdRp activity inhibitor remdesivir has also been investigated in SARS-CoV-2 (Yin et al., 2020).
Remdesivir was originally developed for the treatment for of Ebola virus infection. Remdesivir is covalently incorporated into the primer strand of the virus at the first replicated base pair of RdRp to prevent the chain elongation (Yin et al., 2020). It functions through its active form, metabolite remdesivir triphosphate to compete with the incorporation of nucleotide counterparts and inhibits transcription of viral RNA. Although remdesivir has not shown to reduce the mortality in COVID-19 patients, it appears to accelerate the recovery when its administration was initiated early (Beigel et al., 2020). Remdesivir has been authorized in the USA for patients with severe COVID-19 since a NIH clinical trials demonstrated that it can accelerate the recovery and shorten the hospital stay of severe COVID-19 patients (Beigel et al., 2020). A recent report indicates that remdesivir given within 9 days from symptom-onset was associated with decrease in mortality in moderate-to-severe COVID-19 patients (Mehta, Bansal, Bysani & Kalpakam, 2021).
However, the effectiveness of remdesivir is far from convincing (Brouqui, Giraud-Gatineau & Raoult, 2020). An earlier clinical trial in China did not show significant benefit of remdesivir in severe COVID-19 patients (Wang et al., 2020b). The discrepancy of results between China and the USA has been ascribed to the difference in genetic backgrounds of patients with COVID-19 (Wang, Cui, Ouyang, Zhan, Guo & Yin, 2020). More effective inhibitors of SARS-CoV-1 RdRp are required for better management of COVID-19.