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    Pan- ErbB HGNC inhibition protects from SARS-CoV-2 replication, inflammation MESHD, and injury

    Authors: Sirle Saul; Marwah Karim; Pei Tzu Huang; Luca Ghita; Winston Chiu; Sathish Kumar; Nishank Bhalla; Pieter Leyssen; Courtney A. Cohen; Kathleen E. Huie; Courtney Tindle; Malaya Kumar Sahoo; Mamdouh Sibai; Benjamin A. Pinsky; Soumita Das; Pradipta Ghosh; John Dye; David E. Solow-Cordero; Jing Jin; Dirk Jochmans; Johan Neyts; Aarthi Narayanan; Steven De Jonghe; Shirit Einav

    doi:10.1101/2021.05.15.444128 Date: 2021-05-16 Source: bioRxiv

    Effective therapies are needed to combat emerging viruses. Seventeen candidates that rescue cells from SARS-CoV-2-induced lethality and target diverse functions emerged in a screen of 4,413 compounds. Among the hits was lapatinib, an approved inhibitor of the ErbB HGNC family of receptor tyrosine kinases. Lapatinib and other pan- ErbB HGNC inhibitors suppress replication of SARS-CoV-2 and unrelated viruses with a high barrier to resistance. ErbB4, but not lapatinib's cancer MESHD targets ErbB1 and ErbB2, is required for SARS-CoV-2 entry MESHD and Venezuelan equine encephalitis virus infection MESHD and is a molecular target mediating lapatinib's antiviral effect. In human lung organoids, lapatinib protects from SARS-CoV-2-induced activation of pathways implicated in acute and chronic lung injury MESHD downstream of ErbBs ( p38 HGNC-MAPK, MEK HGNC/ ERK HGNC, and AKT HGNC/ mTOR HGNC), pro-inflammatory cytokine production, and epithelial barrier injury MESHD. These findings reveal regulation of viral infection MESHD, inflammation MESHD, and tissue injury via ErbBs MESHD and propose approved candidates to counteract these effects with implications for coronaviruses and unrelated viruses.

    Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

    Authors: Guoli Shi; Abhilash I Chiramel; Saliha Majdoul; Kin Kui Lai; Sudipto Das; Paul A Beare; Thorkell Andresson; Sonja M Best; Alex A Compton

    doi:10.1101/2021.04.15.440067 Date: 2021-04-16 Source: bioRxiv

    Infection by SARS-CoV-2 generally causes mild symptoms but can lead to severe disease and death MESHD in certain populations, including the immunocompromised. Drug repurposing efforts are underway to identify compounds that interfere with SARS-CoV-2 replication or the immunopathology it can elicit. Rapamycin is among those being currently tested in clinical trials for impacts on COVID-19 MESHD severity. While rapamycin and rapamycin analogs (rapalogs) are FDA-approved for use as mTOR HGNC inhibitors in multiple clinical settings, including cancer MESHD, we previously found that rapamycin can increase the susceptibility of cells to infection by Influenza A virus. In this study, we tested the impact of rapalogs on cellular susceptibility to SARS-CoV-2 infection MESHD. We report that rapamycin and rapalogs increased SARS-CoV-2 titers in human cervical epithelial and lung epithelial cell lines to different extents, and a similar pattern of enhancement was observed using pseudovirus incorporating viral fusion proteins from SARS-CoV-2, SARS-CoV MESHD, MERS, and Influenza A Virus. Rapalogs also promoted cell entry driven by SARS-CoV-2 Spike PROTEIN in nasal cells and primary small airway cells, representing proximal and distal ends of the human respiratory tract, respectively. Interestingly, cell entry enhancement by the rapalog ridaforolimus was cell type-dependent, revealing a previously unrecognized functional divergence between rapalogs. The differential activity of rapalogs was associated with their capacity to induce the degradation of interferon-inducible transmembrane (IFITM) proteins, restriction factors that broadly inhibit virus infection MESHD. Our findings will spur the development of mTOR HGNC inhibitors that do not suppress the first line of antiviral defense in cells.

    Blockade of SARS-CoV-2 infection MESHD in-vitro by highly potent PI3K-α/ mTOR HGNC/ BRD4 HGNC inhibitor

    Authors: Arpan Acharya; Kabita Pandey; Michellie Thurman; Kishore B Challagundla; Kendra R Vann; Tatiana G Kutateladze; Guillermo A Morales; Donald L Durden; Siddappa N Byrareddy

    doi:10.1101/2021.03.02.433604 Date: 2021-03-03 Source: bioRxiv

    Pathogenic viruses like SARS-CoV-2 and HIV hijack the host MESHD molecular machinery to establish infection and survival in infected cells. This has led the scientific community to explore the molecular mechanisms by which SARS-CoV-2 infects MESHD host cells, establishes productive infection, and causes life-threatening pathophysiology. Very few targeted therapeutics for COVID-19 MESHD currently exist, such as remdesivir. Recently, a proteomic approach explored the interactions of 26 of 29 SARS-CoV-2 proteins with cellular targets in human cells and identified 67 interactions as potential targets for drug development. Two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs): BRD2 HGNC/ BRD4 HGNC and mTOR HGNC, are inhibited by the dual inhibitory small molecule SF2523 at nanomolar potency. SF2523 is the only known mTOR HGNC PI3K-/( BRD2 HGNC/ BRD4 HGNC) inhibitor with potential to block two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Our results demonstrate that SF2523 effectively blocks SARS-CoV-2 replication in lung bronchial epithelial cells in vitro, showing an IC50 value of 1.5 {micro}M, comparable to IC50 value of remdesivir (1.1 {micro}M). Further, we demonstrated that the combination of doses of SF2523 and remdesivir is highly synergistic: it allows for the reduction of doses of SF2523 and remdesivir by 25-fold and 4-fold, respectively, to achieve the same potency observed for a single inhibitor. Because SF2523 inhibits two SARS-CoV-2 driven pathogenesis mechanisms involving BRD2 HGNC/ BRD4 HGNC and mTOR HGNC signaling, our data suggest that SF2523 alone or in combination with remdesivir could be a novel and efficient therapeutic strategy to block SARS-CoV-2 infection MESHD and hence be beneficial in preventing severe COVID-19 MESHD disease evolution. One Sentence SummaryEvidence of in silico designed chemotype (SF2523) targeting PI3K-/ mTOR HGNC/ BRD4 HGNC inhibits SARS-CoV-2 infection MESHD and is highly synergistic with remdesivir.

    Molecular Basis of Kidney Defects in COVID-19 MESHD Patients

    Authors: Smartya Pulai; Madhurima Basu; Chinmay Saha; Nitai P. Bhattacharyya; Arpita Ray Chaudhury; Sujoy Ghosh

    id:10.20944/preprints202007.0452.v1 Date: 2020-07-20 Source: Preprints.org

    Background: Kidney damage MESHD is considered to be one of the risk factors for severity and mortality among COVID-19 MESHD patients. However, molecular nature of such observations remains unknown. Hypothesis: Altered gene expressions due to infection and in chronic kidney disease MESHD could explain severity in COVID-19 MESHD with kidney defects MESHD. Methods: We collected gene expression data from publicly available resources Gene Expression Omnibus CKD MESHD, Enrichr for deregulated genes in SARS-CoV infected MESHD cells in vitro, DisGeNET and others and carried out enrichment analysis using Enrichr. Result: Number of common genes altered in chronic kidney disease MESHD ( CKD MESHD) and SARS-CoV infected MESHD cells was 2834. Enrichment analysis revealed that biological processes related viral life cycle and growth, cytokines, immunity, interferon, inflammation MESHD, apoptosis, autophagy, oxidative stress and others were significantly enriched with common deregulated genes. Similarly, significantly enriched pathways related to viral and bacterial infections MESHD, immunity and inflammation MESHD, cell cycle, ubiquitin mediated proteolysis, signaling pathways like Relaxin signaling pathway, mTOR HGNC signaling pathway, IL-17 signaling pathway, NF-kappa B signaling pathway were enriched with the common deregulated genes. These processes and pathways are known to be related to kidney damage MESHD. DisGeNET terms enriched include and related to Dengue fever MESHD, chronic Hepatitis MESHD, measles, retroviridae infections MESHD, respiratory syncytial virus Infections MESHD and many others. Kidney dysfunction MESHD related terms ischemia of kidney, renal fibrosis MESHD and diabetic nephropathy MESHD. Conclusion: Common deregulated genes in SARS-CoV infected MESHD cells and chronic kidney disease MESHD, as well as their enrichment with molecular processes and pathways relevant for viral pathogenesis and renal dysfunctions MESHD, could explain the severity of COVID-19 MESHD with kidney disease MESHD. This observation not only provides molecular relation of severity in COVID-19 MESHD with renal dysfunctions MESHD but might also help in the management and treatment targets for these cases.

    Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection MESHD

    Authors: Komudi Singh; Yun-Ching Chen; Jennifer T. Judy; Fayaz Seifuddin; Ilker Tunc; Mehdi Pirooznia

    doi:10.1101/2020.05.13.092536 Date: 2020-05-14 Source: bioRxiv

    Analyzing host transcriptional changes in response to SARS-CoV-2 infection MESHD will help delineate biological processes underlying viral pathogenesis. Comparison of expression profiles of lung cell lines A549 (infected with either SARS-CoV-2 (with ACE2 expression)) or Influenza A virus (IAV)) and Calu3 (infected with SARS-CoV-2 or MERS-CoV) revealed upregulation of the antiviral interferon signaling in all three viral infections. However, perturbations in inflammatory, mitochondrial, and autophagy processes were specifically observed in SARS-CoV-2 infected MESHD cells. Validation of findings from cell line data revealed perturbations in autophagy and mitochondrial processes in the infected human nasopharyngeal samples. Specifically, downregulation of mTOR HGNC expression, mitochondrial ribosomal, mitochondrial complex I, and lysosome acidification genes were concurrently observed in both infected cell lines and human datasets. Furthermore, SARS-CoV-2 infection MESHD impedes autophagic flux by upregulating GSK3B HGNC in lung cell lines, or by downregulating autophagy genes, SNAP29 HGNC and lysosome acidification genes in human samples, contributing to increased viral replication. Therefore, drugs targeting lysosome acidification or autophagic flux could be tested as intervention strategies. Additionally, downregulation of MTFP1 HGNC (in cell lines) or SOCS6 HGNC (in human samples) results in hyperfused mitochondria and impede proper interferon response. Coexpression networks analysis identifies correlated clusters of genes annotated to inflammation MESHD and mitochondrial processes that are misregulated in SARS-CoV-2 infected MESHD cells. Finally, comparison of age stratified human gene expression data revealed impaired upregulation of chemokines, interferon stimulated and tripartite motif genes that are critical for antiviral signaling. Together, this analysis has revealed specific aspects of autophagic and mitochondrial function that are uniquely perturbed in SARS-CoV-2 infection MESHD.

    Transcriptional landscape of SARS-CoV-2 infection MESHD dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies

    Authors: Paolo Fagone; Rosella Ciurleo; Salvo Danilo Lombardo; Carmelo Iacobello; Concetta Ilenia Palermo; Yehuda Shoenfeld; Klaus Bendtzen; Placido Bramanti; Ferdinando Nicoletti

    id:2005.01042v1 Date: 2020-05-03 Source: arXiv

    The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease MESHD ( COVID-19 MESHD) has posed a serious threat to global health. As no specific therapeutics are yet available to control disease evolution, more in-depth understanding of the pathogenic mechanisms induced by SARS-CoV-2 will help to characterize new targets for the management of COVID-19 MESHD. The present study identified a specific set of biological pathways altered in primary human lung epithelium upon SARS-CoV-2 infection MESHD, and a comparison with SARS-CoV from the 2003 pandemic was studied. The transcriptomic profiles were also exploited as possible novel therapeutic targets, and anti-signature perturbation analysis predicted potential drugs to control disease progression. Among them, Mitogen-activated protein kinase kinase ( MEK HGNC), serine-threonine kinase ( AKT HGNC), mammalian target of rapamycin HGNC ( mTOR HGNC) and I kappa B Kinase (IKK) inhibitors emerged as candidate drugs. Finally, sex-specific differences that may underlie the higher COVID-19 MESHD mortality in men are proposed.

    Dysregulation in mTOR HGNC/ HIF-1 HGNC signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

    Authors: Sofia Appelberg; Soham Gupta; Anoop T Ambikan; Flora Mikaeloff; Akos Vegvari; Sara Svensson Akusjarvi; Rui Benfeitas; Maike Sperk; Marie Stahlberg; Shuba Krishnan; Kamal Singh; Josef M Penninger; Ali Mirazimi; Ujjwal Neogi

    doi:10.1101/2020.04.30.070383 Date: 2020-05-01 Source: bioRxiv

    How Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections MESHD engage cellular host pathways and innate immunity in infected cells remain largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected MESHD HuH7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB HGNC, HIF-1 HGNC, mTOR HGNC and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection MESHD in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of HIF-1 HGNC through the entire time course of the infection, suggesting a crosstalk between the SARS-CoV-2 and the mTOR HGNC/ HIF-1 HGNC signaling. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe COVID-19 MESHD patients.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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