MEK inhibitors as novel host-targeted antivirals with a dual-benefit mode of action against hyperinflammatory respiratory viral diseases

Ludwig, Stephan; Pleschka, Stephan; Planz, Oliver

doi:10.1016/j.coviro.2023.101304

Cited by 8 publications

(10 citation statements)

References 52 publications

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“…Our study’s functional enrichment analysis displayed that DEGs between both influenza (severe and non-severe) cases were primarily associated with pathways with immune response and inflammation-related pathways. Moreover, the ICI analysis revealed a notable impairment in adaptive immune responses among patients afflicted with severe influenza, consistent with prior scientific findings [ 13 , 18 , 19 ]. Nguyen et al [ 13 ] conducted a longitudinal study on patients hospitalized with acute influenza and found that a higher SOFA score was associated with lower adaptive-producing CD8 + T cell responses.…”

Section: Discussionsupporting

confidence: 88%

Bioinformatics analysis identifies a key gene HLA_DPA1 in severe influenza-associated immune infiltration

Chen,

Hua,

2024

BMC Genomics

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Background Severe influenza is a serious global health issue that leads to prolonged hospitalization and mortality on a significant scale. The pathogenesis of this infectious disease is poorly understood. Therefore, this study aimed to identify the key genes associated with severe influenza patients necessitating invasive mechanical ventilation. Methods The current study utilized two publicly accessible gene expression profiles (GSE111368 and GSE21802) from the Gene Expression Omnibus database. The research focused on identifying the genes exhibiting differential expression between severe and non-severe influenza patients. We employed three machine learning algorithms, namely the Least Absolute Shrinkage and Selection Operator regression model, Random Forest, and Support Vector Machine-Recursive Feature Elimination, to detect potential key genes. The key gene was further selected based on the diagnostic performance of the target genes substantiated in the dataset GSE101702. A single-sample gene set enrichment analysis algorithm was applied to evaluate the participation of immune cell infiltration and their associations with key genes. Results A total of 44 differentially expressed genes were recognized; among them, we focused on 10 common genes, namely PCOLCE2, HLA_DPA1, LOC653061, TDRD9, MPO, HLA_DQA1, MAOA, S100P, RAP1GAP, and CA1. To ensure the robustness of our findings, we employed overlapping LASSO regression, Random Forest, and SVM-RFE algorithms. By utilizing these algorithms, we were able to pinpoint the aforementioned 10 genes as potential biomarkers for distinguishing between both cases of influenza (severe and non-severe). However, the gene HLA_DPA1 has been recognized as a crucial factor in the pathological condition of severe influenza. Notably, the validation dataset revealed that this gene exhibited the highest area under the receiver operating characteristic curve, with a value of 0.891. The use of single-sample gene set enrichment analysis has provided valuable insights into the immune responses of patients afflicted with severe influenza that have further revealed a categorical correlation between the expression of HLA_DPA1 and lymphocytes. Conclusion The findings indicated that the HLA_DPA1 gene may play a crucial role in the immune-pathological condition of severe influenza and could serve as a promising therapeutic target for patients infected with severe influenza.

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Section: Discussionsupporting

confidence: 88%

Bioinformatics analysis identifies a key gene HLA_DPA1 in severe influenza-associated immune infiltration

Chen,

Hua,

2024

BMC Genomics

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“…Several articles have described the utilization of the RAF/ MEK/ERK network by various viruses, including influenza [12,[26][27][28]. In case of the SARS-CoV-2 virus, MAPK signaling facilitates virus entry into the cell and promotes virus replication [16]. Therefore, the RAF/MEK/ERK network has been discussed as a valuable target in COVID-19 therapy [16][17][18].…”

Section: Discussionmentioning

confidence: 99%

“…For COVID-19, exploitation of this specific pathway by the SARS-CoV-2 virus has also been identified for the early phase of infection, leading to increased viral replication [14]. Further studies showed that MEK inhibitors, such as those being tested against the influenza virus [15], can also alleviate viral replication of SARS-CoV-2 and subsequent cytokine release, which is considered to be a major driver of critical disease progression [16][17][18]. To date, it is unclear whether the suggested protective effects of a suppressed RAF/MEK/ERK activity are also applicable to the later phase of COVID-19-induced sepsis in humans [19,20].…”

Section: Introductionmentioning

confidence: 99%

Activation of the MAPK network provides a survival advantage during the course of COVID-19-induced sepsis: a real-world evidence analysis of a multicenter COVID-19 Sepsis Cohort

Witowski,

Palmowski,

Rahmel

et al. 2024

Infection

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Purpose There is evidence that lower activity of the RAF/MEK/ERK network is associated with positive outcomes in mild and moderate courses of COVID-19. The effect of this cascade in COVID-19 sepsis is still undetermined. Therefore, we tested the hypothesis that activity of the RAF/MEK/ERK network in COVID-19-induced sepsis is associated with an impact on 30-day survival. Methods We used biomaterial from 81 prospectively recruited patients from the multicentric CovidDataNet.NRW-study cohort (German clinical trial registry: DRKS00026184) with their collected medical history, vital signs, laboratory parameters, microbiological findings and patient outcome. ERK activity was measured by evaluating ERK phosphorylation using a Proximity Ligation Assay. Results An increased ERK activity at 4 days after diagnosis of COVID-19-induced sepsis was associated with a more than threefold increased chance of survival in an adjusted Cox regression model. ERK activity was independent of other confounders such as Charlson Comorbidity Index or SOFA score (HR 0.28, 95% CI 0.10–0.84, p = 0.02). Conclusion High activity of the RAF/MEK/ERK network during the course of COVID-19 sepsis is a protective factor and may indicate recovery of the immune system. Further studies are needed to confirm these results.

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“…Unfortunately, no small molecule kinase inhibitor has been approved as an antiviral till date ( 10 ). A small molecule inhibitor of the mitogen-activated protein kinase (MAPK) kinase (MEK) is currently under phase I clinical trial (NCT04385420) as an anti-infective drug ( 11 – 13 ). Notably, it has completed a phase II study (NCT04776044) tested in COVID-19 patients ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

“…A small molecule inhibitor of the mitogen-activated protein kinase (MAPK) kinase (MEK) is currently under phase I clinical trial (NCT04385420) as an anti-infective drug ( 11 – 13 ). Notably, it has completed a phase II study (NCT04776044) tested in COVID-19 patients ( 13 ). This highlights the knowledge gap that persists in terms of clear understanding of the role of host kinases in modulating the virus replication cycle, which is critical for exploiting them as potential antiviral targets.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the role of host kinases at different steps of influenza A virus life cycle

Dey,

Mondal

2024

J Virol

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Influenza viruses remain a major public health concern causing contagious respiratory illnesses that result in around 290,000–650,000 global deaths every year. Their ability to constantly evolve through antigenic shifts and drifts leads to the emergence of newer strains and resistance to existing drugs and vaccines. To combat this, there is a critical need for novel antiviral drugs through the introduction of host-targeted therapeutics. Influenza viruses encode only 14 gene products that get extensively modified through phosphorylation by a diverse array of host kinases. Reversible phosphorylation at serine, threonine, or tyrosine residues dynamically regulates the structure, function, and subcellular localization of viral proteins at different stages of their life cycle. In addition, kinases influence a plethora of signaling pathways that also regulate virus propagation by modulating the host cell environment thus establishing a critical virus-host relationship that is indispensable for executing successful infection. This dependence on host kinases opens up exciting possibilities for developing kinase inhibitors as next-generation anti-influenza therapy. To fully capitalize on this potential, extensive mapping of the influenza virus-host kinase interaction network is essential. The key focus of this review is to outline the molecular mechanisms by which host kinases regulate different steps of the influenza A virus life cycle, starting from attachment-entry to assembly-budding. By assessing the contributions of different host kinases and their specific phosphorylation events during the virus life cycle, we aim to develop a holistic overview of the virus-host kinase interaction network that may shed light on potential targets for novel antiviral interventions.

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MEK inhibitors as novel host-targeted antivirals with a dual-benefit mode of action against hyperinflammatory respiratory viral diseases

Cited by 8 publications

References 52 publications

Bioinformatics analysis identifies a key gene HLA_DPA1 in severe influenza-associated immune infiltration

Bioinformatics analysis identifies a key gene HLA_DPA1 in severe influenza-associated immune infiltration

Activation of the MAPK network provides a survival advantage during the course of COVID-19-induced sepsis: a real-world evidence analysis of a multicenter COVID-19 Sepsis Cohort

Unveiling the role of host kinases at different steps of influenza A virus life cycle

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