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1.
Sci Rep ; 12(1): 9188, 2022 Jun 02.
Article in English | MEDLINE | ID: covidwho-1873556

ABSTRACT

Several highly effective Covid-19 vaccines are in emergency use, although more-infectious coronavirus strains, could delay the end of the pandemic even further. Because of this, it is highly desirable to develop fast antiviral drug treatments to accelerate the lasting immunity against the virus. From a theoretical perspective, computational approaches are useful tools for antiviral drug development based on the data analysis of gene expression, chemical structure, molecular pathway, and protein interaction mapping. This work studies the structural stability of virus-host interactome networks based on the graphical representation of virus-host protein interactions as vertices or nodes connected by commonly shared proteins. These graphical network visualization methods are analogous to those use in the design of artificial neural networks in neuromorphic computing. In standard protein-node-based network representation, virus-host interaction merges with virus-protein and host-protein networks, introducing redundant links associated with the internal virus and host networks. On the contrary, our approach provides a direct geometrical representation of viral infection structure and allows the effective and fast detection of the structural robustness of the virus-host network through proteins removal. This method was validated by applying it to H1N1 and HIV viruses, in which we were able to pinpoint the changes in the Interactome Network produced by known vaccines. The application of this method to the SARS-CoV-2 virus-host protein interactome implies that nonstructural proteins nsp4, nsp12, nsp16, the nuclear pore membrane glycoprotein NUP210, and ubiquitin specific peptidase USP54 play a crucial role in the viral infection, and their removal may provide an efficient therapy. This method may be extended to any new mutations or other viruses for which the Interactome Network is experimentally determined. Since time is of the essence, because of the impact of more-infectious strains on controlling the spread of the virus, this method may be a useful tool for novel antiviral therapies.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Virus Diseases , Viruses , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 Vaccines , Humans , Influenza A Virus, H1N1 Subtype/metabolism , SARS-CoV-2 , Viral Proteins/metabolism , Viruses/metabolism
2.
Sci Rep ; 12(1): 5867, 2022 04 07.
Article in English | MEDLINE | ID: covidwho-1778626

ABSTRACT

SARS-CoV-2 pandemic first emerged in late 2019 in China. It has since infected more than 298 million individuals and caused over 5 million deaths globally. The identification of essential proteins in a protein-protein interaction network (PPIN) is not only crucial in understanding the process of cellular life but also useful in drug discovery. There are many centrality measures to detect influential nodes in complex networks. Since SARS-CoV-2 and (H1N1) influenza PPINs pose 553 common human proteins. Analyzing influential proteins and comparing these networks together can be an effective step in helping biologists for drug-target prediction. We used 21 centrality measures on SARS-CoV-2 and (H1N1) influenza PPINs to identify essential proteins. We applied principal component analysis and unsupervised machine learning methods to reveal the most informative measures. Appealingly, some measures had a high level of contribution in comparison to others in both PPINs, namely Decay, Residual closeness, Markov, Degree, closeness (Latora), Barycenter, Closeness (Freeman), and Lin centralities. We also investigated some graph theory-based properties like the power law, exponential distribution, and robustness. Both PPINs tended to properties of scale-free networks that expose their nature of heterogeneity. Dimensionality reduction and unsupervised learning methods were so effective to uncover appropriate centrality measures.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Influenza, Human , Humans , Influenza A Virus, H1N1 Subtype/metabolism , Protein Interaction Maps , Proteins/metabolism , SARS-CoV-2
3.
Molecules ; 27(4)2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1715566

ABSTRACT

Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa-, hepta- and octavalent BA derivatives based on α-, ß- and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave-assisted copper-catalyzed 1,3-dipolar cycloaddition reaction. The generated BA-cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested compounds, 58, 80 and 82 showed slight cytotoxicity to Madin-Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 µM. Four conjugates 51 and 69-71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration values of 5.20, 9.82, 7.48 and 7.59 µM, respectively. The structure-activity relationships of multivalent BA-cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection.


Subject(s)
Antiviral Agents , Cyclodextrins/chemistry , Influenza A Virus, H1N1 Subtype/metabolism , Orthomyxoviridae Infections/drug therapy , Pentacyclic Triterpenes/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Dogs , Drug Evaluation, Preclinical , Madin Darby Canine Kidney Cells , Orthomyxoviridae Infections/metabolism , Structure-Activity Relationship
4.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1700574

ABSTRACT

Influenza A virus (IAV) is a member of the single-stranded RNA (ssRNA) family of viruses. The most recent global pandemic caused by the SARS-CoV-2 virus has shown the major threat that RNA viruses can pose to humanity. In comparison, influenza has an even higher pandemic potential as a result of its high rate of mutations within its relatively short (<13 kbp) genome, as well as its capability to undergo genetic reassortment. In light of this threat, and the fact that RNA structure is connected to a broad range of known biological functions, deeper investigation of viral RNA (vRNA) structures is of high interest. Here, for the first time, we propose a secondary structure for segment 8 vRNA (vRNA8) of A/California/04/2009 (H1N1) formed in the presence of cellular and viral components. This structure shows similarities with prior in vitro experiments. Additionally, we determined the location of several well-defined, conserved structural motifs of vRNA8 within IAV strains with possible functionality. These RNA motifs appear to fold independently of regional nucleoprotein (NP)-binding affinity, but a low or uneven distribution of NP in each motif region is noted. This research also highlights several accessible sites for oligonucleotide tools and small molecules in vRNA8 in a cellular environment that might be a target for influenza A virus inhibition on the RNA level.


Subject(s)
Gene Expression Regulation, Viral , Genome, Viral/genetics , Influenza A Virus, H1N1 Subtype/genetics , Nucleic Acid Conformation , RNA, Viral/chemistry , Animals , Base Sequence , Dogs , Humans , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/virology , Madin Darby Canine Kidney Cells , Models, Molecular , Nucleotide Motifs/genetics , RNA Folding , RNA, Viral/genetics , Viral Proteins/genetics , Viral Proteins/metabolism
5.
Sci Rep ; 12(1): 2594, 2022 02 16.
Article in English | MEDLINE | ID: covidwho-1692553

ABSTRACT

Complex glycans decorate viral surface proteins and play a critical role in virus-host interactions. Viral surface glycans shield vulnerable protein epitopes from host immunity yet can also present distinct "glycoepitopes" that can be targeted by host antibodies such as the potent anti-HIV antibody 2G12 that binds high-mannose glycans on gp120. Two recent publications demonstrate 2G12 binding to high mannose glycans on SARS-CoV-2 and select Influenza A (Flu) H3N2 viruses. Previously, our lab observed 2G12 binding and functional inhibition of a range of Flu viruses that include H3N2 and H1N1 lineages. In this manuscript, we present these data alongside structural analyses to offer an expanded picture of 2G12-Flu interactions. Further, based on the remarkable breadth of 2G12 N-glycan recognition and the structural factors promoting glycoprotein oligomannosylation, we hypothesize that 2G12 glycoepitopes can be defined from protein structure alone according to N-glycan site topology. We develop a model describing 2G12 glycoepitopes based on N-glycan site topology, and apply the model to identify viruses within the Protein Data Bank presenting putative 2G12 glycoepitopes for 2G12 repurposing toward analytical, diagnostic, and therapeutic applications.


Subject(s)
Antibodies, Monoclonal/metabolism , Broadly Neutralizing Antibodies/metabolism , HIV Antibodies/metabolism , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/immunology , Models, Immunological , SARS-CoV-2/immunology , Animals , Dogs , Drug Repositioning , Epitopes , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Humans , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H3N2 Subtype/metabolism , Madin Darby Canine Kidney Cells , Molecular Targeted Therapy , Neutralization Tests , Polysaccharides/metabolism
6.
Int J Mol Sci ; 23(1)2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1580700

ABSTRACT

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.


Subject(s)
COVID-19/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Actins/metabolism , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Caveolin 1/metabolism , Collagen Type I/metabolism , Collagen Type III/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Immunohistochemistry , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , Influenza, Human/pathology , Interleukin-4/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Retrospective Studies , Transforming Growth Factor beta1/metabolism
7.
STAR Protoc ; 3(1): 101051, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1575581

ABSTRACT

Here we describe a protocol for identifying metabolites in respiratory specimens of patients that are SARS-CoV-2 positive, SARS-CoV-2 negative, or H1N1 positive. This protocol provides step-by-step instructions on sample collection from patients, followed by metabolite extraction. We use ultra-high-pressure liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS) for data acquisition and describe the steps for data analysis. The protocol was standardized with specific customization for SARS-CoV-2-containing respiratory specimens. For complete details on the use and execution of this protocol, please refer to Maras et al. (2021).


Subject(s)
COVID-19/diagnosis , Chromatography, High Pressure Liquid/methods , Metabolomics/methods , COVID-19/metabolism , Computational Biology , Diagnostic Tests, Routine , Gene Expression Profiling , Genetic Techniques , Humans , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H1N1 Subtype/pathogenicity , Mass Spectrometry/methods , Metabolome , Reference Standards , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Specimen Handling/methods
8.
STAR Protoc ; 3(1): 101045, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1537118

ABSTRACT

In this protocol, we describe global proteome profiling for the respiratory specimen of COVID-19 patients, patients suspected with COVID-19, and H1N1 patients. In this protocol, details for identifying host, viral, or bacterial proteome (Meta-proteome) are provided. Major steps of the protocol include virus inactivation, protein quantification and digestion, desalting of peptides, high-resolution mass spectrometry (HRMS)-based analysis, and downstream bioinformatics analysis. For complete details on the use and execution of this profile, please refer to Maras et al. (2021).


Subject(s)
COVID-19/diagnosis , Genomics/methods , Proteomics/methods , COVID-19/metabolism , Chromatography, Liquid/methods , Computational Biology , Diagnostic Tests, Routine , Gene Expression Profiling , Genetic Techniques , Genome, Viral/genetics , Humans , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H1N1 Subtype/pathogenicity , Peptides , Proteome , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Specimen Handling/methods , Tandem Mass Spectrometry/methods , Virome/genetics , Virome/physiology
9.
Mucosal Immunol ; 14(6): 1224-1234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1387186

ABSTRACT

Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.


Subject(s)
Adipocytes/metabolism , COVID-19/metabolism , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , SARS-CoV-2/metabolism , Adipocytes/pathology , Adipocytes/virology , COVID-19/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/virology , Influenza, Human/pathology
10.
Am J Respir Cell Mol Biol ; 64(6): 677-686, 2021 06.
Article in English | MEDLINE | ID: covidwho-1259048

ABSTRACT

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 µg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 µg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Cytidine Diphosphate Choline/pharmacology , Cytidine Diphosphate Diglycerides/pharmacology , Influenza A Virus, H1N1 Subtype/metabolism , Orthomyxoviridae Infections/drug therapy , Respiratory Distress Syndrome/prevention & control , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Animals , COVID-19/drug therapy , COVID-19/pathology , Mice , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , SARS-CoV-2/metabolism
11.
Front Immunol ; 12: 593595, 2021.
Article in English | MEDLINE | ID: covidwho-1229174

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.


Subject(s)
COVID-19 , Cytokines , Influenza A Virus, H1N1 Subtype , Influenza, Human , Matrix Metalloproteinase 1 , Matrix Metalloproteinase 3 , Receptors, Immunologic , Adult , Aged , COVID-19/blood , COVID-19/epidemiology , COVID-19/immunology , Cytokines/blood , Cytokines/immunology , Female , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/blood , Influenza, Human/epidemiology , Influenza, Human/immunology , Male , Matrix Metalloproteinase 1/blood , Matrix Metalloproteinase 1/immunology , Matrix Metalloproteinase 3/blood , Matrix Metalloproteinase 3/immunology , Middle Aged , Prospective Studies , Receptors, Immunologic/blood , Receptors, Immunologic/immunology , Th1 Cells/immunology , Th2 Cells/immunology
12.
J Med Virol ; 93(4): 2396-2405, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217389

ABSTRACT

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.


Subject(s)
COVID-19/metabolism , Mevalonic Acid/metabolism , SARS-CoV-2/metabolism , A549 Cells , Autophagy , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Computer Simulation , Cytokines/immunology , Cytokines/metabolism , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/metabolism , Influenza, Human/immunology , Influenza, Human/metabolism , SAM Domain and HD Domain-Containing Protein 1/genetics , SAM Domain and HD Domain-Containing Protein 1/metabolism , SARS-CoV-2/genetics , Signal Transduction , Transcriptome , Virus Replication
13.
J Biol Chem ; 296: 100470, 2021.
Article in English | MEDLINE | ID: covidwho-1101336

ABSTRACT

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Dioxanes/pharmacology , Glucosyltransferases/antagonists & inhibitors , Glycosphingolipids/antagonists & inhibitors , Influenza A Virus, H1N1 Subtype/drug effects , Pyrrolidines/pharmacology , Quinuclidines/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/virology , Carbamates/chemical synthesis , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/virology , Chlorocebus aethiops , Clinical Trials, Phase III as Topic , Dioxanes/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gene Expression Regulation , Glucosyltransferases/genetics , Glucosyltransferases/metabolism , Glycosphingolipids/biosynthesis , Host-Pathogen Interactions/genetics , Humans , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/drug therapy , Influenza, Human/enzymology , Influenza, Human/virology , Madin Darby Canine Kidney Cells , Pyrrolidines/chemical synthesis , Quinuclidines/chemical synthesis , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Signal Transduction , Vero Cells , Virus Replication/drug effects
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