Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

SUBMITTER: Liu X

PROVIDER: S-EPMC8552907 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SARSCoV2 host proteome interactions for antiviral drug discovery

Project description:We adopted the MAC (Multiple Approaches Combined) tag system enabling both APMS and BioIDMS analysis with a single construct to perform a comprehensive analysis to map SARSCoV2 host interactome.

2021-03-11 | MSV000087035 | MassIVE

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

Project description: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.

| S-EPMC8662392 | biostudies-literature

Virus-host interactomes--antiviral drug discovery.

Project description:One of the key questions in virology is how viruses, encoding relatively few genes, gain temporary or constant control over their hosts. To understand pathogenicity of a virus it is important to gain knowledge on the function of the individual viral proteins in the host cell, on their interactions with viral and cellular proteins and on the consequences of these interactions on cellular signaling pathways. A combination of transcriptomics, proteomics, high-throughput technologies and the bioinformatical analysis of the respective data help to elucidate specific cellular antiviral drug target candidates. In addition, viral and human interactome analyses indicate that different viruses target common, central human proteins for entering cellular signaling pathways and machineries which might constitute powerful broad-spectrum antiviral targets.

| S-EPMC7102765 | biostudies-literature

Comparison of viral RNA–host protein interactomes across pathogenic RNA viruses informs rapid antiviral drug discovery for SARS-CoV-2

Project description:We profiled vRNA-host protein interactomes for three RNA virus pathogens (SARS-CoV-2, Zika, and Ebola viruses) using ChIRP-MS. Comparative interactome analyses discovered both common and virus-specific host responses and vRNA-associated proteins that variously promote or restrict viral infection. In particular, SARS-CoV-2 binds and hijacks the host factor IGF2BP1 to stabilize vRNA and augment translation. Our interactome-informed drug repurposing efforts identified several FDA-approved drugs (e.g., Cepharanthine) as broad-spectrum antivirals in cells and hACE2 mice. A co-treatment comprising Cepharanthine and Trifluoperazine was highly potent against the newly emerged SARS-CoV-2 B.1.351 variant. Thus, our study illustrates the scientific and medical discovery utility of adopting a comparative vRNA-host protein interactome perspective.

2021-10-10 | GSE181866 | GEO

Production of Proteins of the SARS-CoV-2 Proteome for Drug Discovery.

Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the coronavirus disease of 2019 (COVID-19). Its genome encodes two open reading frames for two large proteins, PP1a and PP1ab. Within the two polypeptide stretches, there are two proteases that process the large proteins into 15 discrete proteins essential for the assembly of the virion during its replication. We describe herein the cloning of the genes for these discrete proteins optimized for expression in Escherichia coli, production of the proteins, and their purification to homogeneity. These included all but six: NSP6, which possesses eight transmembrane regions, and five that are small proteins/peptides (E, ORF3b, ORF6, ORF7b, and ORF10). These proteins are intended for experimental validation of small-molecule binders as molecular template hits. The proof of concept was established with the ADP-ribosylhydrolase (ARH) domain of NSP3 in discovery of small-molecule templates that could serve as the basis for further optimization. The hit molecules include one submicromolar and a few low-micromolar binders to the ARH domain. Availability of these proteins in soluble forms opens up the opportunity for discoveries of novel templates with the potential for anti-COVID-19 pharmaceuticals.

| S-EPMC8315141 | biostudies-literature

Comparison of viral RNA-host protein interactomes across pathogenic RNA viruses informs rapid antiviral drug discovery for SARS-CoV-2.

Project description:In contrast to the extensive research about viral protein-host protein interactions that has revealed major insights about how RNA viruses engage with host cells during infection, few studies have examined interactions between host factors and viral RNAs (vRNAs). Here, we profiled vRNA-host protein interactomes for three RNA virus pathogens (SARS-CoV-2, Zika, and Ebola viruses) using ChIRP-MS. Comparative interactome analyses discovered both common and virus-specific host responses and vRNA-associated proteins that variously promote or restrict viral infection. In particular, SARS-CoV-2 binds and hijacks the host factor IGF2BP1 to stabilize vRNA and augment viral translation. Our interactome-informed drug repurposing efforts identified several FDA-approved drugs (e.g., Cepharanthine) as broad-spectrum antivirals in cells and hACE2 transgenic mice. A co-treatment comprising Cepharanthine and Trifluoperazine was highly potent against the newly emerged SARS-CoV-2 B.1.351 variant. Thus, our study illustrates the scientific and medical discovery utility of adopting a comparative vRNA-host protein interactome perspective.

| S-EPMC8566969 | biostudies-literature

Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions.

Project description:SARS-CoV-2 is the cause of a pandemic with growing global mortality. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with ChIRP-MS data from three other RNA viruses defined viral specificity of RNA-host protein interactions. Targeted CRISPR screens revealed that the majority of functional RNA-binding proteins protect the host from virus-induced cell death, and comparative CRISPR screens across seven RNA viruses revealed shared and SARS-specific antiviral factors. Finally, by combining the RNA-centric approach and functional CRISPR screens, we demonstrated a physical and functional connection between SARS-CoV-2 and mitochondria, highlighting this organelle as a general platform for antiviral activity. Altogether, these data provide a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which may inform studies to understand the host-virus interface and nominate host pathways that could be targeted for therapeutic benefit.

| S-EPMC7951565 | biostudies-literature

Recapitulating hepatitis E virus-host interactions and facilitating antiviral drug discovery in human liver-derived organoids.

Project description:Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.

| S-EPMC8769558 | biostudies-literature

The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation.

| S-EPMC8513853 | biostudies-literature

The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation.

Project description:Viral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 severity, including the TRIM4 interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was associated with inhibited host protein translation whereas ORF6 localization with MAVS was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 protease, with specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2. SARS-CoV-2 is the latest pathogenic coronavirus to emerge as a public health threat. We create a database of proximal host proteins to 17 SARS-CoV-2 viral proteins. We validate that NSP1 is proximal to the EIF3 translation initiation complex and is a potent inhibitor of translation. We also identify ORF6 antagonism of RNA-mediate innate immune signaling. We produce a database of potential host targets of the viral protease NSP5, and create a fluorescence-based assay to screen cleavage of peptide sequences. We believe that this data will be useful for identifying roles for many of the uncharacterized SARS-CoV-2 proteins and provide insights into the pathogenicity of new or emerging coronaviruses.

| S-EPMC7924263 | 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