Kinase Inhibitors as Underexplored Antiviral Agents

García‐Cárceles, Javier; Caballero, Elena; Gil, Carmen; Martı́nez, Ana

doi:10.1021/acs.jmedchem.1c00302

Cited by 46 publications

(39 citation statements)

References 188 publications

(358 reference statements)

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“…For a comprehensive analysis of the antiviral activity of CDK inhibitors and vCDK/pUL97 inhibitors, we selected a broad panel of PKIs, the majority of which are currently investigated at preclinical and clinical levels (https://www.ppu.mrc.ac.uk/list-clinically-approved-kinaseinhibitors; last accessed on 26 January 2022; [22,23]). We focused on PKIs targeting human CDKs 2, 7, 8, 9 as well as vCDK/pUL97, since these kinases have all been shown to exert a relevant regulatory role for efficient HCMV replication [1,5,21,[24][25][26][27][28][29][30][31].…”

Section: Evaluation Of Antiviral Efficacy and Drug-induced Cytotoxici...mentioning

confidence: 99%

Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations

Wild

Hahn

Brückner

et al. 2022

IJMS

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Human cytomegalovirus (HCMV) is a pathogenic human herpesvirus associated with serious, potentially life-threatening symptoms in the immunocompromised or immunonaïve host. The limitations encountered by antiviral therapy options currently available include a narrow panel of accessible targets, the induction of viral drug resistance as well as severe drug dosage‑mediated side‑effects. Improved drug-targeting strategies to resolve these issues are the focus of our investigations. In particular, pharmaceutical kinase inhibitors (PKIs), either directed to host kinases or directed to the viral protein kinase pUL97, have been considered to overcome these restrictions. Recently, we reported the identification of a synergistic combination of two PKIs directed to host cyclin‑dependent kinase 7 (CDK7) and viral CDK ortholog pUL97. Here, we substantiate these findings with the following results: (i) true drug synergy was exhibited by various chemical classes of PKI pairs directed to pUL97 and CDK7; (ii) no putative amplification of cytotoxicity by these drug combinations was observed; (iii) a reduction in drug dosage levels for synergistic combinations was defined on a quantitative basis and compared to monotreatments; (iv) the quantities of target proteins CDK7 and pUL97 expressed in HCMV-infected cells were assessed by confocal imaging, indicating a strong down-modulation of CDK7 levels as a result of synergistic drug treatment; (v) the functional importance of these target kinases, both binding to cyclin H, was illustrated by assessing HCMV replication under the viral genomic deletion of ORF-UL97 or cellular cyclin knock-out; (vi) new combinations of HCMV-specific drug synergy were demonstrated for solely host-directed treatments using PKIs against CDK2, CDK7, CDK8 and/or CDK9 and (vii) a triple PKI combination provided further support for the synergy approach. With these combined findings, this study highlights the potential of therapeutic drug combinations of approved, developmental and preclinical PKIs for expanding future options for anti‑HCMV therapy.

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Section: Evaluation Of Antiviral Efficacy and Drug-induced Cytotoxici...mentioning

confidence: 99%

Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations

Wild

Hahn

Brückner

et al. 2022

IJMS

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show abstract

“…A cost-effective and reduced-risk strategy widely exploited in the last decade to overcome the trickiness of CNS drug discovery is drug repurposing. The rediscovery of "old molecules" fits with the need for poorly addressed therapeutic areas in which the CNS-related pathologies represent a leading field [11,12]. Great examples in this scenario are saracatinib (1) and masitinib (2), which are two well-known inhibitors of FYN kinase firstly developed as anti-cancer agents.…”

Section: The Neurokinome In Drug Discoverymentioning

confidence: 99%

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Demuro

Martino

Ortega

et al. 2021

IJMS

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Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.

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“… 13 , 14 Protein kinases are involved in almost all cell signaling processes and are often induced or suppressed by viruses during infection. 15 Casein Kinase 2 (CSNK2) is a constitutively active serine/threonine kinase typically found as a tetramer consisting of two catalytic subunits and two regulatory subunits, forming either a homotetramer or heterotetramer depending on the identity of the catalytic subunit ( Figure 1 A). 16 CSNK2 phosphorylates hundreds of physiological substrates and modulates the activity of many cell signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Kinase Inhibitors as Underexplored Antiviral Agents

Cited by 46 publications

References 188 publications

Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations

Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

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

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