ArticleNucleic acids research2023
Interfering with nucleotide excision by the coronavirus 3'-to-5' exoribonuclease.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism.The Journal of biological chemistry · 2026Article
- Recovery of proofreading-impaired SARS-CoV-2 reveals a mutator phenotype and an ExoN activity threshold for viability.Journal of virology · 2026Article
- The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism.bioRxiv : the preprint server for biology · 2026Article
- Copy-back RNA synthesis by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir.Science advances · 2026Article
- Recovery of proofreading-impaired SARS-CoV-2 reveals a mutator phenotype and an ExoN activity threshold for viability.bioRxiv : the preprint server for biology · 2026Article
- Template switching by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir.bioRxiv : the preprint server for biology · 2025Article
- A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent.Nucleic acids research · 2025Article
- Viperin: A Multifunctional Protein in Antiviral Immunity and Disease Pathogenesis.Pathogens (Basel, Switzerland) · 2025Review
- The coronavirus nsp14 exoribonuclease interface with the cofactor nsp10 is essential for efficient virus replication and enzymatic activity.Journal of virology · 2025Article
- Despite the odds: formation of the SARS-CoV-2 methylation complex.Nucleic acids research · 2024Article
- An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex.Nucleic acids research · 2024Article
- Therapeutic strategies for COVID-19: progress and lessons learned.Nature reviews. Drug discovery · 2023Review
- Current understanding of nucleoside analogs inhibiting the SARS-CoV-2 RNA-dependent RNA polymerase.Computational and structural biotechnology journal · 2023Review
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
Some of the most efficacious antiviral therapeutics are ribonucleos(t)ide analogs. The presence of a 3'-to-5' proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3'-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3'-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.