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Host Kinase CSNK2 is a Target for Inhibition of Pathogenic SARS-like β-Coronaviruses.

ABSTRACT: Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human, bat, and murine β-coronaviruses. The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in β-coronavirus replication. Spike protein endocytosis was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for the development of anti-SARS-like β-coronavirus drugs.

SUBMITTER: Yang X

PROVIDER: S-EPMC9236220 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Host Kinase CSNK2 is a Target for Inhibition of Pathogenic SARS-like β-Coronaviruses.

Yang Xuan X Dickmander Rebekah J RJ Bayati Armin A Taft-Benz Sharon A SA Smith Jeffery L JL Wells Carrow I CI Madden Emily A EA Brown Jason W JW Lenarcic Erik M EM Yount Boyd L BL Chang Edcon E Axtman Alison D AD Baric Ralph S RS Heise Mark T MT McPherson Peter S PS Moorman Nathaniel J NJ Willson Timothy M TM

ACS chemical biology 20220619 7

Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human, bat, and murine β-coronaviruses. The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in β-coronavirus replication. Spike protein endocytosis was blocked by CSNK2A inhibition, indicating that antiviral ...[more]

PMID: 35723434

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Host kinase CSNK2 is a target for inhibition of pathogenic β-coronaviruses including SARS-CoV-2.

Project description:Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human and murine β-coronaviruses. The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in β-coronavirus replication. Spike protein uptake was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for development of new broad spectrum anti-β-coronavirus drugs.Graphical abstract

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Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-04-02 | GSE213999 | GEO

Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses [RNAseq]

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DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner.

Project description:Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses.

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Project description: Not available

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