• Assay Selection Tool

BellBrook Labs

  • Products
    • Transcreener® HTS Assay Kits
      • Transcreener® ADP² Kinase Assay Kits
        • Transcreener® ADP2 Assay Kit – FP Readout
        • Transcreener® ADP2 Assay Kit – FI Readout
        • Transcreener® ADP2 Assay Kit – TR-FRET Readout
      • Transcreener® ADO CD73 Assay Kit
      • Transcreener® AMP²/GMP² Phosphodiesterase Assay Kits
        • Transcreener® AMP2/GMP2 FP Assay
        • Transcreener® AMP2/GMP2 Assay Kit – TR-FRET Readout
      • Transcreener® cGAMP cGAS Assay Kits
        • Transcreener® cGAMP Assay Kit – FP Readout
        • Transcreener® cGAMP Assay Kit – TR-FRET Readout
      • Transcreener dAMP Exonuclease Assay Kit
      • Transcreener® EPIGEN SAH Methyltransferase Assay Kit
      • Transcreener® GDP GTPase Assay Kits
        • Transcreener® GDP Assay Kit – FP Readout
        • Transcreener® GDP Assay Kit – FI Readout
        • Transcreener® GDP Assay Kit – TR-FRET Readout
      • Transcreener® UDP² Glycosyltransferase Assay Kits
        • Transcreener® UDP2 Assay Kit – FP Readout
        • Transcreener® UDP2 Assay Kit – FI Readout
        • Transcreener® UDP2 Assay Kit – TR-FRET Readout
      • Transcreener® 2-5A OAS Assay Kit
    • AptaFluor® HTS Assay Kits
      • AptaFluor® SAH Methyltransferase Assay Kit
    • Enzyme Assay Systems
      • TREX1 Assay System
    • Recombinant Enzymes
      • Human cGAS Enzyme
      • Mouse cGAS Enzyme
      • Human DDX3 Enzyme
      • Human OAS1 Enzyme
      • Human TREX1 Enzyme
    • Assay Plates
    • Ordering Information
  • Services
    • Assay Development Services
    • Lead Discovery Services
    • CD38 Assay Services
    • GTPase Profiling Services
    • ATPase Profiling Services
  • Assays by Target
    • Kinase Assays
      • ADK Assays – Application
      • AMPK Assays – Application
      • IKK-beta Assays – Application
      • IRAK4 Assays – Application
      • JAK1 Assays – Application
      • JAK3 Assays – Application
      • MAPK8 Assays – Application
      • PKR Assays – Application
      • RIPK1 Assays – Application
      • RIPK2 Assays – Application
      • TBK1 Assays – Application
    • GTPase Assays
      • GAP Assays – Application
      • GEF Assays – Application
      • KRAS Assays – Application
      • HRAS Assays – Application
      • NRAS Assays – Application
      • RRAS Assays – Application
      • Rac1 Assays – Application
      • RhoA Assays – Application
      • RhoC Assays – Application
      • Cdc42 Assays – Application
      • Ran Assays – Application
    • Methyltransferase Assays
      • EZH2 Assays – Application
      • G9a Assays – Application
      • SET7/9 Assays – Application
      • SET8 Assays – Application
      • PRMT1 Assays – Application
      • PRMT3 Assays – Application
      • PRMT4 Assay – Application
    • STING Pathway Assays
      • cGAS Assay Kits
      • ENPP1 Assays – Application
      • TREX1 Assay System
      • IKK-beta Assays – Application
      • TBK1 Assays – Application
    • Nucleotidase Assays
      • CD38 Assay Services
      • CD39 Assays – Application
      • CD73 Activity Assay Kits
    • Helicase / ATPase Assays
      • DDX3 Assays – Application
      • NSP13 Assays – Application
      • P97 Assays – Application
    • Glycosyltransferase Assays
      • Toxin B Assays – Application
      • GALNT2 Assays – Application
      • GALNT3 Assays – Application
      • BGalT1 Assays – Application
    • Phosphodiesterase Assays
      • PDE3 Assays – Application
      • PDE4 Assays – Application
      • PDE5 Assays – Application
      • PDE7 Assays – Application
    • Ligase and Synthetase Assays
      • SUMO E1 Assays – Application
      • Acyl CoA Synthetase Assays – Application
      • S-Acetyl CoA Synthetase Assays – Application
    • Exonuclease Assays
      • TREX1 Assay System
    • OAS Assays
      • OAS1 Assay Kits
    • Other Enzyme Assays
      • NUDT5 Assays – Application
  • Resources
    • Technical Manuals
    • Transcreener® Assays – Instrument Compatibility
    • Application Notes
    • Posters and Presentations
    • Publications
    • Transcreener® FAQ’s
    • Guides
      • Residence Time Guide
      • Hit Prioritization Guide
      • Kinases in Innate Immunity
  • Company
    • President’s Message
    • International Distributors
    • Careers
    • Downloads
    • Contact Us
  • Blog
  • MY CART
    No products in cart.

NSP14 – A Promising SARS-CoV-2 Therapeutic Target

by Bellbrook Labs / Thursday, 20 January 2022 / Published in Emerging Targets, Innate Immunity
NSP14 - Coronavirus Target

Non-Structural Proteins of Coronaviruses

Coronaviruses have complex RNA-synthesizing machinery composed of many non-structural proteins (NSPs). While one-third of the viral genome encodes for structural proteins such as the spike, envelope, and nucleocapsid proteins, the remaining two-thirds encodes for NSPs. NSP genes are located within the 5’-region of the genome and studies have revealed that NSPs play essential roles in multiple viral processes such as RNA synthesis and processing¹.

The Two Faces of NSP14

NSP14 has recently been identified as an important NSP in SARS-CoV-2 virus replication. NSP14 is a unique bi-functional NSP that contains two functional domains – a 3’ to 5’ exoribonuclease (ExoN) at the N-terminus and a guanine-N7-methyltransferase (N7-MTase) domain at the C-terminus². The ExoN domain allows SARS-CoV-2 to proofread by catalyzing nucleoside monophosphate excision from nucleic acids, which is critical for high-fidelity replication. This is especially important for CoV to maintain its large RNA genome by decreasing the rate of harmful mutations. However, this proofreading capability of CoV has hindered the efficacy of antiviral ribonucleoside/ribonucleotide analogs such as remdesivir. Inactivating ExoN was shown to abolish the viability of SARS-CoV-2  effectively³. This is significant because targeting the ExoN activity of SARS-CoV-2 could potentially be an antiviral target for the treatment of COVID-19.

The N7-MTase domain of NSP14 is involved in mRNA capping. This is done by catalyzing the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to the guanosine triphosphate moiety of the newly synthesized viral RNA, forming methylated capped RNA. This 5’ cap promotes RNA stability and translation by preventing degradation by exonucleases and also prevents detection by host innate antiviral responses4.

NSP14 and Innate Immune Responses

How does NSP14 allow CoV to evade host immune responses? 5’ RNA capping mediated by NSP14 allows CoV to mask the pathogen-associated molecular patterns (PAMPs) on the viral genome from being recognized by host immunity by mimicking eukaryotic RNA structures. Uncapped viral RNA is detected by host pattern recognition receptors, which will activate interferon (IFN)-associated antiviral immune responses5.

NSP14-NSP10 Protein-Protein Interactions

Additionally, NSP14 can form a complex with NSP10 (NSP14/10), where NSP10 aids in enhancing the ExoN activity of NSP14. A recent study found that NSP14/10 plays an essential role in inhibiting host translation, which promotes not only viral replication but also stifles immune responses6, therefore allowing CoV to better evade host immunity. Therefore, NSP14/10 poises as an attractive antiviral target to increase SARS-CoV-2  sensitivity towards host immune responses and increase the potency of existing antiviral pharmaceuticals.

References

  1. Yadav, R., Chaudhary, J. K., Jain, N., Chaudhary, P. K., Khanra, S., Dhamija, P., … & Handu, S. (2021). Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells, 10(4), 821. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067447/
  2. Tahir, M. (2021). Coronavirus genomic nsp14‐ExoN, structure, role, mechanism, and potential application as a drug target. Journal of Medical Virology, 93(7), 4258-4264. https://pubmed.ncbi.nlm.nih.gov/33837972/
  3. Ogando, N. S., Zevenhoven-Dobbe, J. C., van der Meer, Y., Bredenbeek, P. J., Posthuma, C. C., & Snijder, E. J. (2020). The enzymatic activity of the nsp14 exoribonuclease is critical for replication of MERS-CoV and SARS-CoV-2. Journal of virology, 94(23), e01246-20. https://journals.asm.org/doi/10.1128/JVI.01246-20
  4. Decroly, E., Ferron, F., Lescar, J., & Canard, B. (2012). Conventional and unconventional mechanisms for capping viral mRNA. Nature Reviews Microbiology, 10(1), 51-65. https://www.nature.com/articles/nrmicro2675
  5. Li, J. Y., Zhou, Z. J., Wang, Q., He, Q. N., Zhao, M. Y., Qiu, Y., & Ge, X. Y. (2021). Innate Immunity Evasion Strategies of Highly Pathogenic Coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2. Frontiers in Microbiology, 12. https://www.frontiersin.org/articles/10.3389/fmicb.2021.770656/full
  6. Hsu, J. C. C., Laurent-Rolle, M., Pawlak, J. B., Wilen, C. B., & Cresswell, P. (2021). Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein. Proceedings of the National Academy of Sciences, 118(24). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214666/
Tagged under: Innate Immunity, NSP14, Transcreener ADP Assay

What you can read next

Bound for Life: The First Irreversible Inhibitor of CDK2
OAS1 The Cost of Host Defense
OAS1: The Cost of Host Defense
Scientist Working on TBK1 Inhibitors for Cancer Research
Using TBK1 Inhibitors to Stop Cancer in Its Tracks

Categories

  • Company
  • Emerging Targets
  • Epigenetics
  • HTS Assays
  • Innate Immunity
  • Neurodegenerative Diseases
  • News
  • Products
  • Resources
  • Success Stories
  • Uncategorized

Recent Posts

  • PARP1 as a Hero vs Villain

    Is PARP1 a Hero or Villain?

    Not counting histones, PARP1 [Poly(ADP-ribose) ...
  • Ongoing Puzzle of c-SRC in Cancer Treatment

    Advancements in The Ongoing Puzzle to Understand c-SRC

    Nearly a half-century ago, sequences from the R...
  • SLAS 2023 Conference Exhibitor Announcement

    SLAS 2023 – HTS Assays and Discovery Services

    BellBrook Labs will exhibit and present posters...
  • BTK's Involved in Systemic lupus erythematosus

    The Challenging Search for BTK Inhibitors

    Bruton’s Tyrosine Kinase (BTK) is a 76kDa...
  • SARM1 Causes Axonal Death

    SARM1 Forefronts Research into Major Neurological Diseases

    SARM1 [Sterile alpha & toll/interleukin rec...

Archives

BellBrook Labs
5500 Nobel Drive, Suite 230
Madison, Wisconsin 53711 USA
(608) 443-2400

info@bellbrooklabs.com

 Copyright © 2023 BellBrook Labs | All Rights Reserved | Privacy Policy | Terms of Use | FCOI | Sitemap

TOP