SARS-CoV-2 RNA polymerase as target for antiviral therapy

Abstract

A new human coronavirus named SARS-CoV-2 was identified in several cases of acute respiratory syndrome in Wuhan, China in December 2019. On March 11 2020, WHO declared the SARS-CoV-2 infection to be a pandemic, based on the involvement of 169 nations. Specific drugs for SARS-CoV-2 are obviously not available. Currently, drugs originally developed for other viruses or parasites are currently in clinical trials based on empiric data. In the quest of an effective antiviral drug, the most specific target for an RNA virus is the RNA-dependent RNA-polymerase (RdRp) which shows significant differences between positive-sense and negative-sense RNA viruses. An accurate evaluation of RdRps from different viruses may guide the development of new drugs or the repositioning of already approved antiviral drugs as treatment of SARS-CoV-2. This can accelerate the containment of the SARS-CoV-2 pandemic and, hopefully, of future pandemics due to other emerging zoonotic RNA viruses.

Fig. 1

Alignment of amino acid sequences from RdRp of RNA viruses. a Sequences from positive-sense SARS-CoV-2, SARS-CoV and MERS viruses; b Sequences as in (a) with the addition of positive-sense viruses HCV, Dengue, West Nile, Zika and Yellow Fever viruses; c Sequences from positive-sense coronaviruses and negative-sense viruses Influenza, Ebola, Rabies, Vesicular Stomatitis virus, Measle, LCMV, Respirovirus and Orthopneumovirus. Red dots indicate 100% conservation of the indicated aa residues. Red asterisks indicate 100% conservation among HCV and human coronaviruses. Motif B and C of the RdRp are indicated

Fig. 1

Alignment of amino acid sequences from RdRp of RNA viruses. a Sequences from positive-sense SARS-CoV-2, SARS-CoV and MERS viruses; b Sequences as in (a) with the addition of positive-sense viruses HCV, Dengue, West Nile, Zika and Yellow Fever viruses; c Sequences from positive-sense coronaviruses and negative-sense viruses Influenza, Ebola, Rabies, Vesicular Stomatitis virus, Measle, LCMV, Respirovirus and Orthopneumovirus. Red dots indicate 100% conservation of the indicated aa residues. Red asterisks indicate 100% conservation among HCV and human coronaviruses. Motif B and C of the RdRp are indicated

Fig. 2

Structure modelling of the RdRps. a RdRp structures were derived from PDB databank: SARS-CoV-2 (6M71), Influenza virus (6QCT); HCV (3MWV). The whole molecules are presented independently or superimposed. b Zoomin of the SARS-CoV-2 and HCV core molecules highlighting in red color the conserved residues. Modelling was performed with Molsoft Browser

Fig. 3

Structure modelling of the RdRps. RdRp structures were derived from PDB databank and modelling was performed as described in Fig. 2. a External surface and internal structures of RdRps were compared. b SARS-CoV-2 RdRp; c HCV RdRp; d Influenza RdRp, zoomingin the channel in which the Motif C protrudes (black empty circle). Each of the latter three panels shows three different snapshots in a clockwise rotation

Fig. 3

Structure modelling of the RdRps. RdRp structures were derived from PDB databank and modelling was performed as described in Fig. 2. a External surface and internal structures of RdRps were compared. b SARS-CoV-2 RdRp; c HCV RdRp; d Influenza RdRp, zoomingin the channel in which the Motif C protrudes (black empty circle). Each of the latter three panels shows three different snapshots in a clockwise rotation