SARS-CoV-2 Exoribonuclease (NSP14) As a Potential Therapeutic Target to Treat COVID-19

Although the global health emergency caused by SARS-CoV-2 has led to unprecedented health and socioeconomic crisis, as of today neither an antiviral treatment has been approved for COVID-19, nor is a vaccine available. Like other coronaviruses, SARS-CoV-2 encodes a 3’-5’ exoribonuclease whose proofreading activity contributes to the maintenance of its large genome integrity and stability. The viral exonuclease shares biochemical and structural properties with cellular DnaQ-like exonucleases, suggesting that it was snatched by an ancestral coronavirus. Structural superpositions of the viral exonuclease with its cellular homologs exhibit a remarkable degree of conservation. Accordingly, inhibition mechanisms targeting the catalytic core may block both the cellular and viral exonucleases. Although the SARS-CoV-2 exonuclease has received little attention in the struggle against the COVID-19 pandemic, molecular docking assay suggests that inhibitors of cellular exonucleases may have antiviral activity. Hence, we argue that drug development and testing should consider SARS-CoV-2’s exonuclease as a therapeutic target.