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SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation

ABSTRACT: SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation

PROVIDER: PRJNA1302786 | ENA |

REPOSITORIES: ENA

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SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation

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

SARS-CoV-2 NSP14 Inhibitor Confers Potent Antiviral Efficacy and Reverses NSP14-triggered Host Cell Modulation

Project description:SARS-CoV-2 NSP14 Inhibitor Confers Potent Antiviral Efficacy and Reverses NSP14-triggered Host Cell Modulation

| PRJNA1226168 | ENA

SARS-CoV-2 NSP14 Inhibitor Confers Potent Antiviral Efficacy and Reverses NSP14-triggered Host Cell Modulation

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

Natural product inhibition of SARS-CoV-2 guanine-N7 RNA cap methyltransferase shows potent cellular antiviral efficacy

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:SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation

| PRJNA1321334 | ENA

Micronanoparticled risedronate exhibits potent vaccine adjuvant effects

Project description:Micronanoparticled risedronate exhibits potent vaccine adjuvant effects

| PRJNA1000475 | ENA

Micronanoparticled risedronate exhibits potent vaccine adjuvant effects [RNA-Seq]

Project description:Micronanoparticled risedronate exhibits potent vaccine adjuvant effects [RNA-Seq]

| PRJNA1000477 | ENA

Micronanoparticled risedronate exhibits potent vaccine adjuvant effects [scRNA-Seq]

Project description:Micronanoparticled risedronate exhibits potent vaccine adjuvant effects [scRNA-Seq]

| PRJNA1000479 | ENA

A novel compound exhibits potent anti-Candida albicans activity

Project description:A novel compound exhibits potent anti-Candida albicans activity

| PRJNA1213729 | ENA

SIRT5 is a proviral factor that interacts with SARS-CoV-2 Nsp14 protein

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

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