A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase

Abstract

The outbreaks of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in 2019, have highlighted the concerns about the lack of potential vaccines or antivirals approved for inhibition of CoVs infection. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) which is almost preserved across different viral species can be a potential target for development of antiviral drugs, including nucleoside analogues (NA). However, ExoN proofreading activity of CoVs leads to their protection from several NAs. Therefore, potential platforms based on the development of efficient NAs with broad-spectrum efficacy against human CoVs should be explored. This study was then aimed to present an overview on the development of NAs-based drug repurposing for targeting SARS-CoV-2 RdRp by computational analysis. Afterwards, the clinical development of some NAs including Favipiravir, Sofosbuvir, Ribavirin, Tenofovir, and Remdesivir as potential inhibitors of RdRp, were surveyed. Overall, exploring broad-spectrum NAs as promising inhibitors of RdRp may provide useful information about the identification of potential antiviral repurposed drugs against SARS-CoV-2.

Keywords: Antiviral; COVID-19; Drug; Nucleoside analogue; SARS-CoV-2.

Fig. 1

(A) The life cycle of different RNA viruses via the RdRp (1). (B) Structure of RdRp (PDB ID: 1KHW), (i) motifs, (ii) ribbon structure, (iii) conserved homomorphs, (iv) functional motifs (3). (C) Different inhibition mechanisms by NA (4). (D) Prodrug activation Sofosbuvir and the inhibition of RdRp.

Fig. 2

(A) The binding domain of different protein sequences of SARS-CoV-2 predicted by heat-map analysis. (B) The visualization of 3D structure based on a ribbon model. (i) 3C-like protease, (ii) Papain-like protease, (iii) RdRp [58]. (C) Docking study of different nucleoside analogue and SARS-CoV-2 RdRp. (i) Schematic representation, (ii) binding energy calculation and contribution of residues [67].

Fig. 3

Schematic representation of two different modes of action of Remdesivir. At low concentration of ATP, the RdRp-Remdesivir complex is formed which competitively inhibits the binding of ATP to RdRp. At high concentration, Remdesivir is incorporated in the first transcribe and compromises the uptake of UTP in the second transcribe resulting in chain termination.