Targeting coronaviral nsp14: a bifunctional enzyme for RNA capping and proofreading

Over the past thirty years, coronaviruses (CoVs) have caused several pandemics, posing significant public health and economic burdens. Although the development of vaccines and the emergence of antiviral therapeutics have played a crucial role in mitigating pandemics caused by CoVs, there is an urgent need for alternative strategies to combat potential future pandemics. CoVs possess the largest genomes of all known RNA viruses, and they employ a proofreading mechanism mediated by nsp14 ExoN to maintain the fidelity of their genomes. Additionally, the N7-MTase of nsp14 can catalyze the formation of a cap(0) structure (^7MeGpppA) that allows the virus to evade 5’-3’ ExoN-mediated hydrolysis in host cells. Therefore, as a bifunctional enzyme, nsp14 is a promising potential target for inhibiting viral proliferation. Here, we review the functions of CoV nsp14 and their underlying molecular basis, highlighting the potential and importance of nsp14 as a drug target. We also describe the existing small molecules known to interfere with the ExoN or MTase activity of nsp14, providing inspiration for the development of anti-CoV agents.