RNASeq profiling of COVID19‐infected patients identified an EIF2AK2 inhibitor as a potent SARS‐CoV‐2 antiviral

Jain, Sidharth; Rego, Samantha; Park, Steven; Liu, Yiran; Parn, Simone; Savsani, Kush; Perlin, David S.; Dakshanamurthy, Sivanesan

doi:10.1002/ctm2.1098

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…Similar to findings reported for infectious pancreatic necrosis virus (IPNV) (75), and SARS-CoV-2 (76) treatment with the PKR inhibitor C16 resulted in strong inhibition of LCMV multiplication in WT A549, supporting the role of PKR in LCMV multiplication, and uncovering PKR activation as a druggable target for the development of antiviral drugs against human pathogenic mammarenaviruses, including LCMV for which evidence indicates it is a neglected human pathogen of clinical significance (4–8), and a serious risk to immunocompromised individuals (9, 10). C16 has shown tolerability and efficacy in a mouse model of HCV-induced hepatocarcinogenesis (77), supporting its future evaluation, beyond the scope of the present work, in mouse models of LCMV infection.…”

Section: Discussionsupporting

confidence: 82%

Activation of Protein Kinase R (PKR) Plays a Pro-Viral Role in Mammarenavirus Infected Cells

Witwit,

Khafaji,

Salaniwal

et al. 2023

Preprint

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Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double strand (ds)RNA sensor protein kinase receptor (PKR) pathway plays a critical role in the cell antiviral response. Whether PKR can restrict the multiplication of the Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) and the mechanisms by which LCMV may counteract the antiviral functions of PKR have not yet been investigated. Here we present evidence that LCMV infection results in very limited levels of PKR activation, but LCMV multiplication is enhanced in the absence of PKR. In contrast, infection with a recombinant LCMV with a mutation affecting the 3’-5’ exonuclease (ExoN) activity of the viral nucleoprotein (NP) resulted in robust PKR activation in the absence of detectable levels of dsRNA, which was associated with severely restricted virus multiplication that was alleviated in the absence of PKR. However, pharmacological inhibition of PKR activation resulted in reduced levels of LCMV multiplication. These findings uncovered a complex role of the PKR pathway in LCMV-infected cells involving both pro-and anti- viral activities.IMPORTANCEAs with many other viruses, the prototypic Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) can interfere with the host cell innate immune response to infection, which includes the double strand (ds)RNA sensor protein kinase receptor (PKR) pathway. A detailed understanding of LCMV-PKR interactions can provide novel insights about mammarenavirus-host cell interactions and facilitate the development of effective antiviral strategies against human pathogenic mammarenaviruses. In the present work, we present evidence that LCMV multiplication is enhanced in PKR- deficient cells, but pharmacological inhibition of PKR activation unexpectedly resulted in severely restricted propagation of LCMV. Likewise, we document a robust PKR activation in LCMV-infected cells in the absence of detectable levels of dsRNA. Our findings have revealed a complex role of the PKR pathway during LCMV infection and uncovered the activation of PKR as a druggable target for the development of antiviral drugs against human pathogenic mammarenaviruses.

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Section: Discussionsupporting

confidence: 82%

Activation of Protein Kinase R (PKR) Plays a Pro-Viral Role in Mammarenavirus Infected Cells

Witwit,

Khafaji,

Salaniwal

et al. 2023

Preprint

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“…Significant To our knowledge, this is the largest peripheral transcriptomics study in hospitalized COVID-19 patients who develop AKI. Our results show that COVID-AKI is associated with molecular perturbations within the regulatory markers of endoplasmic reticulum (ER) stress, 31 tubular injury, mitochondrial dysfunction, and oxidative phosphorylation. Some pathways are also found to be common to those with sepsis-AKI including Hypoxia Signaling in the Cardiovascular System, ERK/MAPK Signaling, Unfolded protein response, and IL-1 signaling.…”

Section: Characterization Of Post-acute Kidney Dysfunctionmentioning

confidence: 83%

“…42 Additionally, viral infection acts via the eIF2α pathway to cause global inhibition of translation while Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection upregulating proinflammatory cytokines. 31,42 The mTOR pathway is intertwined with the activation of ER stress response via eukaryotic initiation factor (eIF2/4 complex). 43,44 As a viable target for therapeutic intervention, rapamycin, an inhibitor of mTOR signaling, has been shown to offer a protective effect against progression in rodent models of CKD.…”

Section: These Pathways Have Previously Been Implicated In Aki Develo...mentioning

confidence: 99%

Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection

Jayaraman,

Rajagopal,

Paranjpe

et al. 2023

Preprint

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Background. Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored. Methods. In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells (PBMCs). We applied linear models accounting for technical and biological variability on RNA-Seq data accounting for false discovery rate (FDR) and compared the functional enrichment and pathway results to a historical sepsis-AKI cohort. Finally, we evaluated the association of these signatures with long-term trends in kidney function. Results. Of 283 patients, 106 had AKI. After adjustment for sex, age, mechanical ventilation, and chronic kidney disease (CKD), we identified 2635 significant differential gene expressions at FDR<0.05. Top canonical pathways were EIF2 signaling, oxidative phosphorylation, mTOR signaling, and Th17 signaling, indicating mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Comparison with sepsis associated AKI showed considerable overlap of key pathways (48.14%). Using follow-up estimated glomerular filtration rate (eGFR) measurements from 115 patients, we found that 164/2635 (6.2%) of the significantly differentiated genes were associated with overall decrease in long-term kidney function. The strongest associations were autophagy, renal impairment via fibrosis and cardiac structure/function. Conclusions. We show that AKI in SARS-CoV2 is a multifactorial process with mitochondrial dysfunction driven by ER stress whereas long-term kidney function decline is associated with cardiac structure and function, and immune dysregulation. Functional overlap with sepsis-AKI also highlights common signatures indicating generalizability in therapeutic approaches.

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“…183 Another study by Sidharth Jain et al discovered that C16 is a dual inhibitor of EIF2AK and SARS-CoV-2N, exhibiting strong antiviral activity. 187 Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). The SARS-CoV-2 NSP2 protein impedes Ifnb1 mRNA translation by hijacking the GIGYF2/4EHP complex.…”

Section: Infectious Diseasesmentioning

confidence: 99%

Protein translation: biological processes and therapeutic strategies for human diseases

Jia,

He,

Huang

et al. 2024

Sig Transduct Target Ther

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Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis. The deregulation of this process is increasingly recognized as a critical factor in the pathogenesis of various human diseases. In this review, we discuss how deregulated translation can lead to aberrant protein synthesis, altered cellular functions, and disease progression. We explore the key mechanisms contributing to the deregulation of protein translation, including functional alterations in translation factors, tRNA, mRNA, and ribosome function. Deregulated translation leads to abnormal protein expression, disrupted cellular signaling, and perturbed cellular functions- all of which contribute to disease pathogenesis. The development of ribosome profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing and single-cell approaches have opened new avenues for detecting diseases related to translation errors. Importantly, we highlight recent advances in therapies targeting translation-related disorders and their potential applications in neurodegenerative diseases, cancer, infectious diseases, and cardiovascular diseases. Moreover, the growing interest lies in targeted therapies aimed at restoring precise control over translation in diseased cells is discussed. In conclusion, this comprehensive review underscores the critical role of protein translation in disease and its potential as a therapeutic target. Advancements in understanding the molecular mechanisms of protein translation deregulation, coupled with the development of targeted therapies, offer promising avenues for improving disease outcomes in various human diseases. Additionally, it will unlock doors to the possibility of precision medicine by offering personalized therapies and a deeper understanding of the molecular underpinnings of diseases in the future.

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RNASeq profiling of COVID19‐infected patients identified an EIF2AK2 inhibitor as a potent SARS‐CoV‐2 antiviral

Cited by 6 publications

References 11 publications

Activation of Protein Kinase R (PKR) Plays a Pro-Viral Role in Mammarenavirus Infected Cells

Activation of Protein Kinase R (PKR) Plays a Pro-Viral Role in Mammarenavirus Infected Cells

Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection

Protein translation: biological processes and therapeutic strategies for human diseases

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