Coronavirus genomic nsp14-ExoN, structure, role, mechanism, and potential application as a drug target

Abstract

The recent coronavirus disease 2019 (COVID-19), causing a global pandemic with devastating effects on healthcare and social-economic systems, has no special antiviral therapies available for human coronaviruses (CoVs). The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) possesses a nonstructural protein (nsp14), with amino-terminal domain coding for proofreading exoribonuclease (ExoN) that is required for high-fidelity replication. The ability of CoVs during genome replication and transcription to proofread and exclude mismatched nucleotides has long hindered the development of anti-CoV drugs. The resistance of SARS-CoV-2 to antivirals, especially nucleoside analogs (NAs), shows the need to identify new CoV inhibition targets. Therefore, this review highlights the importance of nsp14-ExoN as a target for inhibition. Also, nucleoside analogs could be used in combination with existing anti-CoV therapeutics to target the proofreading mechanism.

Keywords: RNA recombination; coronavirus; exoribonuclease; nonstructural protein 14; proofreading.

Figure 1

Single‐stranded RNA genome of severe acute respiratory syndrome coronavirus 2. Two‐thirds of the genome encodes two major polyproteins, pp1a and pp1ab, which are divided into 16 nonstructural proteins ⁴⁰

Figure 2

Structure model of severe acute respiratory syndrome coronavirus nsp10/nsp14 complex. From a side view and 90° rotation concerning the side view, ribbon structures of nsp10 (green) and nsp14 (purple) Each protein's amino‐terminal and carboxyl‐terminal extremities are indicated by the letters N and C with their respective colors ³⁸

Figure 3

Schematic describing ExoN proofreading activity and mode of action of inhibitors. (Left Panel) Replication in viruses like Hepatitis C Virus (HCV), with no proofreading mechanism. (Mid panel) Replication in viruses like SARS‐CoV with proofreading Exoribonuclease. (Right panel) It is the same as a mid‐panel but in an ExoN inhibitor ⁵¹