Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1321334 | ENA |
REPOSITORIES: ENA
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Project description:SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
| PRJNA1302786 | ENA
Project description:SARS-CoV-2 virus mimics host mRNA by capping its viral RNA to promote replication and evade host immune sensing. SARS-CoV-2 NSP14 is the N7-guanosine methyltransferase (N7-MTase) responsible for RNA cap-0 formation. Targeting NSP14 for antiviral drug development is an under-explored but promising strategy. Here we conducted a high-throughput screening on natural products library derived from Chinese herbal medicine to discover Emodin as a SARS-CoV-2 NSP14 inhibitor. Exploring Emodin derivatives, Questin was identified with potent cellular inhibitory activity (EC50=249 nM) against SARS-CoV-2, which inhibits NSP14 in an RNA cap competitive manner, making it one the most potent anti-coronaviral natural products. Mechanistically, besides catalyzing viral RNA capping, NSP14 by itself could remodel host transcriptome such as enriching CREBBP, a key host factor in cellular cyclic AMP response pathway, to promote viral infection. As a result, targeting NSP14 by Questin significantly impairs viral Replication & Translation step and reverses host transcriptome remodeled by NSP14. We next validated Questin as a promising lead with significantly improved toxicity upon acute exposure in zebrafish larvae. Taken together, our study not only demonstrates Questin as a potent drug lead for clinical antiviral application, but also highlights multiple antiviral potentials of NSP14 as therapeutic target.
2024-12-31 | GSE282879 | GEO
Project description:The emergence of SARS-CoV-2 variants and drug-resistant mutants underscores the urgent need for novel antiviral therapeutics. SARS-CoV-2 NSP14, an N7-guanosine methyltransferase, plays a critical role in viral RNA capping, enabling viral replication and immune evasion. While NSP14 has emerged as a promising drug target, its role in host-virus crosstalk and the cellular consequences of NSP14 inhibition remain poorly understood. Here, we present the identification and characterization of C10, a highly potent and selective first-in-class non-nucleoside inhibitor of the NSP14 S-adenosylmethionine (SAM)-binding pocket. C10 demonstrates robust antiviral activity against SARS-CoV-2, including its variants, with EC50 values ranging from 64.03 to 301.9 nM, comparable to the FDA-approved drug remdesivir in our cell-based assays. C10 also exhibits broad-spectrum activity against other betacoronaviruses and directly suppresses SARS-CoV-2 genomic replication. C10 specifically reversed NSP14-mediated alterations in host transcriptome and restored host cell cycle progression disrupted by NSP14. The antiviral efficacy of C10 was further validated in a transgenic mouse model of SARS-CoV-2 infection. Our findings highlight C10 as a promising candidate for the development of effective treatments against SARS-CoV-2 and its emerging variants. This study also uncovers a novel mechanism of NSP14 in SARS-CoV-2 pathogenesis and its therapeutic potential, providing insights that may extend to other viral capping methyltransferases.
2025-09-06 | GSE304814 | GEO
Project description:SARS-CoV-2 NSP14 Inhibitor Confers Potent Antiviral Efficacy and Reverses NSP14-triggered Host Cell Modulation
| PRJNA1226168 | ENA
Project description:The emergence of SARS-CoV-2 variants and drug-resistant mutants necessitates additional antivirals. SARS-CoV-2 NSP14 N7-guanosine methyltransferase is responsible for viral RNA capping, facilitating replication and evading immune detection. NSP14 has emerged as a promising drug target, but the role of NSP14 in host-virus crosstalk and the cellular effects of NSP14 inhibition are poorly understood. Here, we performed structure-based virtual screen to identify non-nucleoside inhibitors targeting NSP14 SAM-binding pocket. Hit to Lead optimization resulted in the development of C10 that potently inhibited SARS-CoV-2 and variants with the EC50 values from 64.03 to 301.9 nM, comparable to FDA-approved drug remdesivir in our cell-based model. C10 is a selective inhibitor of β-coronavirus NSP14 and directly suppresses SARS-CoV-2 replication, as demonstrated by a SARS-CoV-2 replicon system. C10 specifically reversed NSP14-mediated host transcriptome alterations and, phenotypically, restored host cell cycle progression disrupted by NSP14. The antiviral efficacy of C10 was further validated in a transgenic mouse model of SARS-CoV-2 infection. Our findings indicate C10 holds promise for developing effective treatments against SARS-CoV-2 and emerging variants, as well as uncover a novel pathogenic role of NSP14 beyond its function in viral RNA capping, which may be also adaptable to other viral capping methyltransferase.
2025-09-06 | GSE290079 | GEO
Project description:The continued emergence of SARS-CoV-2 variants and persistent inflammatory complications of COVID-19 highlight the urgent need for therapeutics with both antiviral and anti-inflammatory properties. Despite intensive global efforts, no approved antiviral therapy with these dual functions has yet been developed, representing a significant gap in current COVID-19 treatment strategies. In this study, we identify BAY 11-7082 (BAY) as a dual–action compound that inhibits SARS-CoV-2 replication and the production of virus-induced proinflammatory cytokines and chemokines, including IL-6, IL-8, CXCL1, and CXCL2. BAY predominantly exerts its antiviral activity at the post-entry stage of the viral life cycle. Mechanistically, BAY potentially interacts with SARS-CoV-2 NSP14 and inhibits virus-induced phosphorylation and degradation of IκBα, suppressing NF-κB activation through the IKK-IκBα signaling axis. Furthermore, BAY exhibits potent antiviral activity against multiple SARS-CoV-2 variants of concern (VOCs). Collectively, these findings support the potential of BAY as a dual-action therapeutic candidate, combining antiviral and anti-inflammatory effects, against SARS-CoV-2 and its emerging variants.
2026-04-03 | GSE310111 | GEO
Project description:The continued emergence of SARS-CoV-2 variants and persistent inflammatory complications of COVID-19 highlight the urgent need for therapeutics with both antiviral and anti-inflammatory properties. Despite intensive global efforts, no approved antiviral therapy with these dual functions has yet been developed, representing a significant gap in current COVID-19 treatment strategies. In this study, we identify BAY 11-7082 (BAY) as a dual–action compound that inhibits SARS-CoV-2 replication and the production of virus-induced proinflammatory cytokines and chemokines, including IL-6, IL-8, CXCL1, and CXCL2. BAY predominantly exerts its antiviral activity at the post-entry stage of the viral life cycle. Mechanistically, BAY potentially interacts with SARS-CoV-2 NSP14 and inhibits virus-induced phosphorylation and degradation of IκBα, suppressing NF-κB activation through the IKK-IκBα signaling axis. Furthermore, BAY exhibits potent antiviral activity against multiple SARS-CoV-2 variants of concern (VOCs). Collectively, these findings support the potential of BAY as a dual-action therapeutic candidate, combining antiviral and anti-inflammatory effects, against SARS-CoV-2 and its emerging variants.
2026-04-03 | GSE310278 | GEO
Project description:SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues. Here we investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection. We showed that SIRT5 stably interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes. We found that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.
2021-12-19 | MSV000088589 | MassIVE
Project description:SARS-CoV-2, the causative agent of COVID-19, manipulates host gene expression through multiple mechanisms, including disruption of RNA processing. Here, we identify a novel function of the viral nonstructural protein 14 (NSP14) in inducing N7-methylguanosine (m7G) modification in the internal sequences of host mRNA. We demonstrate that NSP14 catalyzes the conversion of guanosine triphosphate (GTP) to m7GTP, which is subsequently incorporated into mRNA by RNA polymerase II, resulting in widespread internal m7G modification. This activity is dependent on NSP14's N7-methyltransferase (N7-MTase) domain and is enhanced by interaction with NSP10. Internal m7G modification by NSP14 predominantly occurs in the nucleus and is conserved across alpha-, beta- and gamma-coronaviruses. Mechanistically, we show that this RNA modification disrupts normal splicing by promoting intron retention and generating novel splice junctions. Importantly, inhibition of m7G modification, through pharmacological targeting of NSP14 or RNA polymerase II, impairs SARS-CoV-2 replication, indicating that the virus hijacks host transcriptomic machinery to support infection. Our findings reveal a previously unrecognized epitranscriptomic mechanism by which coronaviruses reprogram host gene expression and suggest that NSP14-induced m7G modification is a potential therapeutic target.
2025-09-05 | GSE307386 | GEO
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the host–virus dependencies are vital for the identification and rational design of effective antiviral therapy. Here, we report the dominant SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) through a proteome-wide protein interaction analysis. We further demonstrate that E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. Pharmacological intervention of ACE2 SUMOylation blocks the entry of SARS-CoV-2 and viral infection-triggered immune responses. Collectively, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination can be targeted to future antiviral therapy of SARS-CoV-2.
2022-07-18 | GSE171130 | GEO