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

Yang, Xuan; Dickmander, Rebekah J.; Bayati, Armin; Taft-Benz, Sharon; Smith, Jeffery L.; Wells, Carrow; Madden, Emily A.; Brown, Jason W.; Lenarcic, Erik M.; Yount, Boyd; Chang, Edcon; Axtman, Alison D.; Baric, Ralph S.; Heise, Mark T.; McPherson, Peter S.; Moorman, Nathaniel J.; Willson, Timothy M.

doi:10.1101/2022.01.03.474779

Cited by 3 publications

(16 citation statements)

References 46 publications

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“…BCoV has common characteristics with SARS-CoV-2—both belong to the β-CoV genus and infect respiratory tract and intestine [ 39 , 40 ]. Protein kinase CK2 has been confirmed as a fundamental factor in some steps of the β-CoV life cycle [ 12 , 13 ]. Recently, the interaction of CK2 with the SARS-CoV-2 nucleocapsid protein has been described, which is conserved in MERS-CoV and SARS-CoV [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Within host factors that viruses hijack during the infection process, kinases proteins play a fundamental role by phosphorylating viral and host substrates [ 11 ]. Recently, protein kinase CK2 has emerged as a relevant therapeutic target in the treatment of β-CoV infections, supported by its genetic and pharmacologic inhibition [ 12 , 13 ]. Remarkably, during SARS-CoV-2 infection CK2 interacts with the N protein, and this protein kinase was found dramatically upregulated in infected cells.…”

Section: Introductionmentioning

confidence: 99%

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Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection

Ramón

Perez

Caballero

et al. 2022

Viruses

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Coronaviruses constitute a global threat to the human population; therefore, effective pan-coronavirus antiviral drugs are required to tackle future re-emerging virus outbreaks. Protein kinase CK2 has been suggested as a promising therapeutic target in COVID-19 owing to the in vitro antiviral activity observed after both pharmacologic and genetic inhibition of the enzyme. Here, we explored the putative antiviral effect of the anti-CK2 peptide CIGB-325 on bovine coronavirus (BCoV) infection using different in vitro viral infected cell-based assays. The impact of the peptide on viral mRNA and protein levels was determined by qRT-PCR and Western blot, respectively. Finally, pull-down experiments followed by Western blot and/or mass spectrometry analysis were performed to identify CIGB-325-interacting proteins. We found that CIGB-325 inhibited both the cytopathic effect and the number of plaque-forming units. Accordingly, intracellular viral protein levels were clearly reduced after treatment of BCoV-infected cells, with CIGB-325 determined by immunocytochemistry. Pull-down assay data revealed the physical interaction of CIGB-325 with viral nucleocapsid (N) protein and a group of bona fide CK2 cellular substrates. Our findings evidence in vitro antiviral activity of CIGB-325 against bovine coronavirus as well as some molecular clues that might support such effect. Altogether, data provided here strengthen the rationale of inhibiting CK2 to treat betacoronavirus infections.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection

Ramón

Perez

Caballero

et al. 2022

Viruses

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“…Since moving from the six-to seven-membered system was accompanied by gains in PIKfyve potency (1 versus AMG28, 4 versus 5, 7 versus 8, 10 versus 11, and 12 versus 13), attachment of the dimethylamino group to the seven-membered core as well as further exploration of the tolerance of PIKfyve to amine-bearing substitution was planned. The seven-membered equivalent of 16 was prepared (17) as well as analogs of AMG28 with the hydroxyl group replaced with an acyl amine (18) or a sulfonamide (19).…”

Section: Diversifying the Terminal Alkynementioning

confidence: 99%

“…We evaluated each of these analogs (17-26) using the DiscoverX scanMAX panel and in the PIKfyve NanoBRET assay. The nitrogen-bearing analogs (17)(18)(19) demonstrated good kinomewide selectivity, binding with PoC values <10 to 9 or fewer WT human kinases at 1 μM. The PIKfyve potency of these compounds, however, was vastly different in both the DiscoverX and NanoBRET assays.…”

Section: Diversifying the Terminal Alkynementioning

confidence: 99%

“…[4][5][6] We made use of a previously developed β-coronavirus assay to explore the activity of our compounds versus published PIKfyve inhibitors on β-coronavirus replication. 18 This assay employs a fusion of mouse hepatitis virus (MHV) with nanoLuciferase (nLuc) to yield MHV-nLuc virus. MHV belongs to the β-coronavirae genus along with SARS-CoV-2.…”

Section: Pikfyve Inhibition Prevents β-Coronavirus Replicationmentioning

confidence: 99%

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Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

Drewry

Potjewyd

Smith

et al. 2022

Preprint

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From a designed library of indolyl pyrimidinamines we identified a highly potent and cell-active chemical probe (analog 17) that inhibits phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). Comprehensive evaluation of inhibitor selectivity confirmed that this PIKfyve probe demonstrates excellent kinome-wide selectivity. A structurally related indolyl pyrimidinamine (analog 30) was characterized as a suitable negative control analog that lacks PIKfyve inhibitory activity and exhibits exquisite selectivity when profiled against the screenable human kinome. Our chemical probe disrupts multiple phases of the life cycle of β-coronaviruses. We observed potent inhibition of viral replication, reduced viral entry, and impacts on a mediator of viral transmission (lysosomes). Our scaffold is a distinct chemotype versus published PIKfyve inhibitors and lacks the canonical morpholine hinge-binder of classical lipid kinase inhibitors. Our chemical probe set can be used by the community to characterize the role of PIKfyve in virology and beyond.

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Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

et al. 2022

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The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC 50 0.79 μM) while also showing a reduction of >3 log TCID 50 /mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1β caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.

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

Cited by 3 publications

References 46 publications

Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection

Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection

Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

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