Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic

Abstract

As of today, there is no antiviral for the treatment of the SARS-CoV-2 infection, and the development of a vaccine might take several months or even years. The structural superposition of the hepatitis C virus polymerase bound to sofosbuvir, a nucleoside analog antiviral approved for hepatitis C virus infections, with the SARS-CoV polymerase shows that the residues that bind to the drug are present in the latter. Moreover, a multiple alignment of several SARS-CoV-2, SARS and MERS-related coronaviruses polymerases shows that these residues are conserved in all these viruses, opening the possibility to use sofosbuvir against these highly infectious pathogens.

Figure 1

Three-dimensional structure of the SARS-CoV RNA-dependent RNA-polymerase (nsp12) and its palm subdomain. (a) The RdRp subdomains are colored as follows: thumb – red; palm – green; fingers – yellow; nidovirus RdRp-associated nucleotidyl transferase (NIRAN) domain – blue; interface – cyan. (b) The conserved structural motifs within the palm subdomain and conforming the active site are colored as follows: motif F – orange; motif A – yellow; motif B – blue; motif C – green; motif D – magenta; motif E – cyan.

Figure 2

Conservation of the Sofosbuvir binding residues in members of the Betacoronavirus genus and structural superposition of SARS-Coronavirus nsp12 with hepatitis C virus NS5B bound to Sofosbuvir. (a) Multiple alignment of SARS-CoV-2 nsp12 and other coronaviruses including SARS-CoV and MERS-related coronavirus. The colored lines below the alignment mark the different structural motifs and are the same as Fig. 1; the residues that partake in Sofosbuvir binding are highlighted in orange, whereas the catalytic aspartates are highlighted in red. (b) The structural superposition of the two polymerases (HCV NS5B is colored blue; SARS-CoV nsp12 is colored yellow) shows the high degree of conservation in the active site. The sidechains of the residues partaking in Sofosbuvir binding are shown, and sofosbuvir is colored orange.