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The coronavirus disease 2019 (COVID-19) that is wreaking havoc on worldwide public health and economies has heightened awareness about the lack of effective antiviral treatments for human coronaviruses (CoVs). Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogs and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently creating a global health emergency. This crisis is driving a worldwide effort to develop effective vaccines, prophylactics, and therapeutics. Nucleic acid (NA)-based treatments hold great potential to combat outbreaks of coronaviruses (CoVs) due to their rapid development, high target specificity, and the capacity to increase druggability. Here, we review key anti-CoV NA-based technologies, including antisense oligonucleotides (ASOs), siRNAs, RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas), and mRNA vaccines, and discuss improved delivery methods and combination therapies with other antiviral drugs. Nucleic-acid based therapies are worth developing against coronavirus (CoV) outbreaks because of their high specificity and rapid development. Several key therapeutic nucleic acid (TNA) strategies, including antisense oligonucleotides (ASOs), siRNA, and RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas) technologies targeting the viral genome are potentially applicable to combat CoVs. mRNA vaccines are attractive candidates to control CoV outbreaks with rapid/easy manufacturing, high potency, and safety. Optimal therapeutic cocktails comprising different TNAs or TNAs with other antiviral agents could act on multiple targets simultaneously, thereby enhancing antiviral effects and reducing risk of drug resistance. Lipid-ASO (LASO) nanomicelles enable cellular self-uptake and can be conjugated with antiviral molecules, providing promising anti-CoV combinational therapeutics that can be delivered directly to the lungs by aerosol. Advancement in chemical modifications and delivery vehicles remarkably enhance stability and pharmacokinetic profile of TNAs, facilitating clinical application of numerous TNAs; however, more studies on optimal chemical manufacturing and delivery methods improving safety and efficiency for TNAs are needed. [ABSTRACT FROM AUTHOR]