ArticleNucleic acids research2023
Crystal structures and fragment screening of SARS-CoV-2 NSP14 reveal details of exoribonuclease activation and mRNA capping and provide starting points for antiviral drug development.
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 35 papers.
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Who cites it
35 citing papers in PubMed.
- Discovery of a 4'-Azido Fleximer Nucleoside Analog With Broad-Spectrum Antiviral Activity Against DENV, EBOV, and Other RNA Viruses.ChemMedChem · 2026Article
- Structural and Mechanistic Perspectives on SARS-CoV-2 Nonstructural Protein 14-Mediated Cap Formation and Drug Discovery.Microorganisms · 2026Review
- Coronavirus NSP14 drives internal m7G modification to rewire host splicing and promote viral replication.Nucleic acids research · 2026Article
- X-ray Crystallography-Guided Design and Synthesis of Cyclopentyl Heteroaryl Carboxylic Acid-Based Inhibitors of the SARS-CoV-2 Nsp3 Macrodomain (Mac1).Journal of medicinal chemistry · 2026Article
- Targeting SARS-CoV-2 Non-Structural Proteins: A Blueprint for Next-Generation Small-Molecule Coronavirus Antivirals.Pharmaceutics · 2026Review
- Dual antiviral and anti-inflammatory effects of BAY 11-7082 in SARS-CoV-2 infection via inhibition of the canonical NF-κB signaling pathway.Scientific reports · 2026Article
- Fragment-Based Development of NSP14 Exonuclease Inhibitors Confounded by Batch-to-Batch Variability.ACS chemical biology · 2026Article
- Antiviral drug discovery and development: challenges and future directions.Signal transduction and targeted therapy · 2026Review
- Article
- Defining substrate specificities of human RNA capping methyltransferases through quantitative assessment of independent yet cooperative activities.Protein science : a publication of the Protein Society · 2026Article
- Broad-spectrum antiviral activity of ebselen.Scientific reports · 2025Article
- Pathogenicity, virological features, and immune evasion of SARS-CoV-2 JN.1-derived variants including JN.1.7, KP.2, KP.3, and KP.3.1.1.Nature communications · 2025Article
- SARS-CoV-2 and HCoV-OC43 regulate host m6A modification via activation of the mTORC1 signalling pathway to facilitate viral replication.Emerging microbes & infections · 2025Article
- SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation.Nature communications · 2025Article
- Unique Features and Collateral Immune Effects of mRNA-LNP COVID-19 Vaccines: Plausible Mechanisms of Adverse Events and Complications.Pharmaceutics · 2025Review
- Iron-sulfur clusters in SARS-CoV-2 exoribonuclease and methyltransferase complexes: relevance for viral genome proofreading and capping.Nature communications · 2025Article
- Au(I)-based compounds inhibit nsp14/nsp10 and nsp13 (helicase) to exert anti-SARS-CoV-2 properties.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2025Article
- Unveiling the structural and functional implications of uncharacterized NSPs and variations in the molecular toolkit across arteriviruses.NAR genomics and bioinformatics · 2025Article
- Delineating cysteine-reactive compound modulation of cellular proteostasis processes.Nature chemical biology · 2025Article
- The coronavirus nsp14 exoribonuclease interface with the cofactor nsp10 is essential for efficient virus replication and enzymatic activity.Journal of virology · 2025Article
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Funding
Abstract
NSP14 is a dual function enzyme containing an N-terminal exonuclease domain (ExoN) and C-terminal Guanine-N7-methyltransferase (N7-MTase) domain. Both activities are essential for the viral life cycle and may be targeted for anti-viral therapeutics. NSP14 forms a complex with NSP10, and this interaction enhances the nuclease but not the methyltransferase activity. We have determined the structure of SARS-CoV-2 NSP14 in the absence of NSP10 to 1.7 Å resolution. Comparisons with NSP14/NSP10 complexes reveal significant conformational changes that occur within the NSP14 ExoN domain upon binding of NSP10, including helix to coil transitions that facilitate the formation of the ExoN active site and provide an explanation of the stimulation of nuclease activity by NSP10. We have determined the structure of NSP14 in complex with cap analogue 7MeGpppG, and observe conformational changes within a SAM/SAH interacting loop that plays a key role in viral mRNA capping offering new insights into MTase activity. We perform an X-ray fragment screen on NSP14, revealing 72 hits bound to sites of inhibition in the ExoN and MTase domains. These fragments serve as excellent starting point tools for structure guided development of NSP14 inhibitors that may be used to treat COVID-19 and potentially other future viral threats.
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