A rapid response to a cluster of patients affected with pneumonia of unknown cause in Wuhan, China, in December 2019, led to the identification, isolation and sequencing of the SARS-CoV–2. This virus belongs to the genus Betacoronavirus (family Coronaviridae),, which also includes the SARS and MERS-CoVs, which caused epidemics in 2002–2003 and 2012, respectively. Infections by these viruses had higher mortality rates compared to the current COVID–19 outbreak: 9.5%, 34%, and 2.5%, respectively [1–3].
In recent years we have witnessed the outbreaks of other “emergent” RNA viruses, including the influenza A(H1N1)pdm09 in 2009, ebola in 2014 and 2018–2019, and zika in 2016, in addition to the endemic dengue and yellow fever viral outbursts, which annually infect hundreds of thousands of patients in tropical regions . Combined with their high mutation rates, large population sizes and fast replicative cycles, RNA viral populations quickly explore a vast number of mutational landscapes, which can lead to the emergence of new infectious viruses in humans or viruses with different pathogenic properties. In contrast with other RNA viruses, coronaviruses and other families of the Nidovirales order encode for a 3’–5’ exoribonuclease (ExoN) with proofreading activity (nsp14), which diminishes their mutation rate, and is one of the key factors that explains why they are endowed with the longest linear genomes in the RNA virosphere .
As of today, there are no broad-spectrum antivirals available to treat the vast majority of the emergent RNA viral infections. This is due to the extreme variability of RNA viral proteomes and the absence of conserved therapeutic targets at which antivirals could be aimed. Current efforts to counteract the SARS-CoV–2 are focused on the proteases and the RNA-dependent RNA polymerase (RdRp) . Previous studies have shown that HIV–1 protease inhibitors Lopinavir/Ritonavir plus Ribavirin (a viral mutagen) had better clinical outcomes compared to Ribavirin alone in SARS-coronavirus infected patients . Currently, a randomized clinical trial is taking place at the Guangzhou 8th People’s Hospital to ascertain the efficacy of Lopinavir/Ritonavir against the SARS-CoV–2 (Clinicaltrials.gov identifier: NCT04252885).
The most highly conserved protein in all known RNA viruses is the viral monomeric RdRp. The coronavirus replication machinery is a large multi-subunit complex; however, the polymerase domain (nsp12) has the characteristic right-hand shape with fingers, thumb and palm subdomains, and the six conserved structural motifs (Figure 1) . Structural and phylogenetic analysis indicate that all known viral RdRps are monophyletic and preserve a high degree of structural conservation, in which key residues within six conserved structural motifs partake in the correct nucleotide recognition and incorporation . Nowadays, there are several drugs that bind to the RdRp active site and that have been approved to treat other RNA viral diseases, including Favipiravir  and Remdesivir . Two clinical trials (Chinese clinical trial identifiers: ChiCTR2000029600 and ChiCTR2000029544) are currently underway in China to test the effectiveness of Favipiravir against SARS-CoV–2. The adenosine analogue Remdesivir has been shown to be efficacious preventing different coronaviral infections in mice, and viral populations lacking the ExoN activity are more sensitive to the drug . Recently, this drug proved to be effective blocking SARS- CoV–2 infection in vitro 13].
Sofosbuvir (SOF) is a nucleotide analogue targeted against the HCV polymerase, NS5B. The structure of HCV bound to SOF  reveals that the drug binds to the active site and is incorporated into the nascent strand preventing the addition of the next nucleotide. The residues that participate in SOF binding include motif A’s D225, motif B’s S282, T287, and N291 (the latter binds to the SOF 2’-F), motif F’s K141 and R158, plus motif A’s and C’s universally conserved aspartates that coordinate the metal ions . Previous work has shown that SOF has in vitro and/or in vivo antiviral activity against other Flaviviruses, i.e. Dengue, Zika, and the West Nile Virus [15–17]. The RdRp structural conservation extends beyond the Flaviviridae members.