Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

SARS-CoV-2-host cell surface interactions and potential antiviral therapies.

ABSTRACT: In this review, we reveal the latest developments at the interface between SARS-CoV-2 and the host cell surface. In particular, we evaluate the current and potential mechanisms of binding, fusion and the conformational changes of the spike (S) protein to host cell surface receptors, especially the human angiotensin-converting enzyme 2 (ACE2) receptor. For instance, upon the initial attachment, the receptor binding domain of the S protein forms primarily hydrogen bonds with the protease domain of ACE2 resulting in conformational changes within the secondary structure. These surface interactions are of paramount importance and have been therapeutically exploited for antiviral design, such as monoclonal antibodies. Additionally, we provide an insight into novel therapies that target viral non-structural proteins, such as viral RNA polymerase. An example of which is remdesivir which has now been approved for use in COVID-19 patients by the US Food and Drug Administration. Establishing further understanding of the molecular details at the cell surface will undoubtably aid the development of more efficacious and selectively targeted therapies to reduce the burden of COVID-19.

SUBMITTER: Butnariu AB

PROVIDER: S-EPMC8662392 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SARS-CoV-2-host proteome interactions for antiviral drug discovery.

Project description:Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP-MS) and the complementary proximity-based labeling MS method (BioID-MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS-CoV-2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image-based drug screen with infectious SARS-CoV-2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein-protein interactions.

| S-EPMC8552907 | biostudies-literature

Targeting SARS-CoV-2 and host cell receptor interactions.

Project description:Despite the availability of vaccines and therapeutics, continual genetic alterations render the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) a persistent threat, particularly for the immunocompromised and elderly. Through interactions of its spike (S) protein with different receptors and coreceptors on host cell surfaces, the virus enters the cell either via fusion with the plasma membrane or through endocytosis. Angiotensin-converting enzyme 2 (ACE2) has been identified as a key receptor utilized by SARS-CoV-2 and related human coronaviruses to mediate cell entry in the lung airways. Auxiliary SARS-CoV-2 entry receptors such as ASGPR1, Kremen protein 1, integrins have also been reported. In this review, therapeutic approaches to block SARS-CoV-2 and host cell receptor interactions are discussed.

| S-EPMC9792186 | biostudies-literature

FBA reveals guanylate kinase as a potential target for antiviral therapies against SARS-CoV-2.

Project description:MotivationThe novel coronavirus (SARS-CoV-2) currently spreads worldwide, causing the disease COVID-19. The number of infections increases daily, without any approved antiviral therapy. The recently released viral nucleotide sequence enables the identification of therapeutic targets, e.g. by analyzing integrated human-virus metabolic models. Investigations of changed metabolic processes after virus infections and the effect of knock-outs on the host and the virus can reveal new potential targets.ResultsWe generated an integrated host-virus genome-scale metabolic model of human alveolar macrophages and SARS-CoV-2. Analyses of stoichiometric and metabolic changes between uninfected and infected host cells using flux balance analysis (FBA) highlighted the different requirements of host and virus. Consequently, alterations in the metabolism can have different effects on host and virus, leading to potential antiviral targets. One of these potential targets is guanylate kinase (GK1). In FBA analyses, the knock-out of the GK1 decreased the growth of the virus to zero, while not affecting the host. As GK1 inhibitors are described in the literature, its potential therapeutic effect for SARS-CoV-2 infections needs to be verified in in-vitro experiments.Availability and implementationThe computational model is accessible at https://identifiers.org/biomodels.db/MODEL2003020001.

| S-EPMC7773487 | biostudies-literature

Network for network concept offers new insights into host- SARS-CoV-2 protein interactions and potential novel targets for developing antiviral drugs.

Project description:SARS-CoV-2, the causal agent of COVID-19, is primarily a pulmonary virus that can directly or indirectly infect several organs. Despite many studies carried out during the current COVID-19 pandemic, some pathological features of SARS-CoV-2 have remained unclear. It has been recently attempted to address the current knowledge gaps on the viral pathogenicity and pathological mechanisms via cellular-level tropism of SARS-CoV-2 using human proteomics, visualization of virus-host protein-protein interactions (PPIs), and enrichment analysis of experimental results. The synergistic use of models and methods that rely on graph theory has enabled the visualization and analysis of the molecular context of virus/host PPIs. We review current knowledge on the SARS-COV-2/host interactome cascade involved in the viral pathogenicity through the graph theory concept and highlight the hub proteins in the intra-viral network that create a subnet with a small number of host central proteins, leading to cell disintegration and infectivity. Then we discuss the putative principle of the "gene-for-gene and "network for network" concepts as platforms for future directions toward designing efficient anti-viral therapies.

| S-EPMC9055686 | biostudies-literature

Immune-Epithelial Cell Cross-Talk Enhances Antiviral Responsiveness to SARS-CoV-2 in Children

Project description:The risk of developing severe COVID-19 rises dramatically with age. Schoolchildren are significantly less likely than older people to die from SARS-CoV-2 infection, but the molecular mechanisms underlying this age-dependence are unknown. In primary infections, innate immunity is critical due to the lack of immune memory. Children, in particular, have a significantly stronger interferon response due to a primed state of their airway epithelium. In single-cell transcriptomes of nasal turbinates, we find increased frequencies of immune cells and stronger cytokine-mediated interactions with epithelial cells, resulting in increased epithelial expression of viral sensors (RIG-I, MDA5) via IRF1. In vitro, adolescent PBMCs produce more cytokines, priming A549 cells for stronger interferon responses to SARS-CoV-2. Taken together, our findings suggest that increased numbers of immune cells in the airways of children and enhanced cytokine-based interactions with epithelial cells tune the set-point of the epithelial antiviral system. Our findings shed light on the molecular basis of children's remarkable resistance to COVID-19 and may suggest a novel concept for immunoprophylactic treatments.

| S-SCDT-10_15252-EMBR_202357912 | biostudies-other

Potential Antiviral Options against SARS-CoV-2 Infection.

Project description:As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

| S-EPMC7354438 | biostudies-literature

Potential antiviral effects of pantethine against SARS-CoV-2.

Project description:SARS-CoV-2 interacts with cellular cholesterol during many stages of its replication cycle. Pantethine was reported to reduce total cholesterol levels and fatty acid synthesis and potentially alter different processes that might be involved in the SARS-CoV-2 replication cycle. Here, we explored the potential antiviral effects of pantethine in two in vitro experimental models of SARS-CoV-2 infection, in Vero E6 cells and in Calu-3a cells. Pantethine reduced the infection of cells by SARS-CoV-2 in both preinfection and postinfection treatment regimens. Accordingly, cellular expression of the viral spike and nucleocapsid proteins was substantially reduced, and we observed a significant reduction in viral copy numbers in the supernatant of cells treated with pantethine. In addition, pantethine inhibited the infection-induced increase in TMPRSS2 and HECT E3 ligase expression in infected cells as well as the increase in antiviral interferon-beta response and inflammatory gene expression in Calu-3a cells. Our results demonstrate that pantethine, which is well tolerated in humans, was very effective in controlling SARS-CoV-2 infection and might represent a new therapeutic drug that can be repurposed for the prevention or treatment of COVID-19 and long COVID syndrome.

| S-EPMC9906591 | biostudies-literature

Therapeutic potential of miRNAs targeting SARS-CoV-2 host cell receptor ACE2.

Project description:In late December 2019, several cases of pneumonia of unknown etiology (COVID-19) were reported in Wuhan, Hubei province, China. Based on clinical findings, blood tests and chest radiographs, this disease was diagnosed as a virus-associated pneumonia. Sequence analysis revealed a novel coronavirus, called SARS-CoV-2 (formerly called 2019-nCoV), as the causative agent of pneumonia of unknown etiology. So far, the SARS-CoV-2 infection continues to spread, and this virus poses a serious public health threat. In this study, it was aimed to reveal potential miRNA targets for the regulation of SARS-CoV-2 host cell receptor ACE2. For the identification of potential miRNA targets for the ACE2 gene, TarBase v.8 (DIANA Tools), TargetScan, miRTarBase and miRDB miRNA-target prediction algorithms were used. FANTOM5 CAGE was used for the cellular ontology analysis. Expression levels of these miRNAs were determined using OncomiR Pan-Cancer miRNome Atlas. The results suggest that members of miR-200 family of miRNAs, especially miR-200c-3p, are strong candidate targets for the regulation of ACE2 in respiratory system cells. Consequently, the present study for the first time emphasizes potential use of miRNA-based therapeutics in the battle against SARS-CoV-2 infection and its deadly disease, COVID-19.

| S-EPMC7672338 | biostudies-literature

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

Project description:The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNAseq to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of cell types are susceptible to infection, ciliated cells are a predominant cell target for SARS-CoV-2. Remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. We also found that heavily infected epithelial cells demonstrate impaired IFN signaling and express abundant IL-6, a potential mediator of COVID-19 pathogenesis.

2020-11-02 | GSE157526 | GEO

SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor.

Project description:Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.

| S-EPMC10110937 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data