Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Individuating Possibly Repurposable Drugs and Drug Targets for COVID-19 Treatment Through Hypothesis-Driven Systems Medicine Using CoVex.

ABSTRACT: Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has developed into a pandemic causing major disruptions and hundreds of thousands of deaths in wide parts of the world. As of July 3, 2020, neither vaccines nor approved drugs for effective treatment are available. In this article, we showcase how to individuate drug targets and potentially repurposable drugs in silico using CoVex a recently presented systems medicine platform for COVID-19 drug repurposing. Starting from initial hypotheses, CoVex leverages network algorithms to individuate host proteins involved in COVID-19 disease mechanisms, as well as existing drugs targeting these potential drug targets. Our analysis reveals GLA, PLAT, and GGCX as potential drug targets, and urokinase, argatroban, dabigatran etexilate, betrixaban, ximelagatran and anisindione as potentially repurposable drugs.

SUBMITTER: Matschinske J

PROVIDER: S-EPMC7703307 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection.

Project description:Understanding the mechanism of SARS-CoV-2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID-19. These were deduced from the gene expression signature of SARS-CoV-2-infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral-host interactome. We also identified immuno-modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID-19 patients, based on the transcriptome of ACE2-overexpressing A549 cells. Experiments with Vero-E6 cells infected by SARS-CoV-2, as well as independent syncytia formation assays for probing ACE2/SARS-CoV-2 spike protein-mediated cell fusion using HEK293T and Calu-3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero-E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID-19.

| S-EPMC8328275 | biostudies-literature

Strategies to identify candidate repurposable drugs: COVID-19 treatment as a case example.

Project description:Drug repurposing is an invaluable strategy to identify new uses for existing drug therapies that overcome many of the time and financial costs associated with novel drug development. The COVID-19 pandemic has driven an unprecedented surge in the development and use of bioinformatic tools to identify candidate repurposable drugs. Using COVID-19 as a case study, we discuss examples of machine-learning and signature-based approaches that have been adapted to rapidly identify candidate drugs. The Library of Integrated Network-based Signatures (LINCS) and Connectivity Map (CMap) are commonly used repositories and have the advantage of being amenable to use by scientists with limited bioinformatic training. Next, we discuss how these recent advances in bioinformatic drug repurposing approaches might be adapted to identify repurposable drugs for CNS disorders. As the development of novel therapies that successfully target the cause of neuropsychiatric and neurological disorders has stalled, there is a pressing need for innovative strategies to treat these complex brain disorders. Bioinformatic approaches to identify repurposable drugs provide an exciting avenue of research that offer promise for improved treatments for CNS disorders.

| S-EPMC8594646 | biostudies-literature

Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation.

Project description:Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36-0.64, p < 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug.

| S-EPMC9588904 | biostudies-literature

Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19?

Project description:Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.

| S-EPMC8450353 | biostudies-literature

Drug Repurposing Approach, Potential Drugs, and Novel Drug Targets for COVID-19 Treatment.

Project description:Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.

| S-EPMC8063850 | biostudies-literature

Identification of Repurposable Drugs and Adverse Drug Reactions for Various Courses of COVID-19 Based on Single-Cell RNA Sequencing Data.

Project description:Coronavirus disease 2019 (COVID-19) has impacted almost every part of human life worldwide, posing a massive threat to human health. There is no specific drug for COVID-19, highlighting the urgent need for the development of effective therapeutics. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating the gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from mild and severe COVID-19 patients. We identified 281 FDA-approved drugs that have the potential to be effective against SARS-CoV-2 infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus. In conclusion, we have identified a list of repurposable anti-SARS-CoV-2 drugs using a systems biology approach.

| S-EPMC7724679 | biostudies-literature

Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach.

Project description:The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.

| S-EPMC7904823 | biostudies-literature

Host - virus - drug interactions as determinants of COVID-19's phenotypes: A data-driven hypothesis.

Project description:There is a growing body of evidence on the significance of interactions between comorbidities, their treatments and COVID-19 clinical phenotypes. The hypothesis explored herein is that pharmaceutical compounds currently in use are affecting COVID-19 susceptibility and phenotypes by overlapping transcriptional networks. Using two distinct SARS-CoV-2 - host interactomes, gene set enrichment analysis is used to discover compounds and assorted gene signatures derived from SARS-CoV-2 interactomes. Micronutrients, antiplatelets, ACE2 inhibitors, NSAIDs, corticosteroids and tyrosine kinase inhibitors are among the compounds discovered. Considering the implication of their associated comorbidities such as diabetes and cardiovascular disease that are associated with severe COVID-19, this study outlines the need to consider specific compounds as modulators of the observed COVID-19 spectrum. Furthermore, given that micronutrient trafficking may be targeted by viral processes, and display synergism with other enriched compounds, such as statins, studies assessing their levels prior and during infection are more than warranted.

| S-EPMC7494558 | biostudies-literature

Potentially repurposable drugs for schizophrenia identified from its interactome.

Project description:We previously presented the protein-protein interaction network of schizophrenia associated genes, and from it, the drug-protein interactome which showed the drugs that target any of the proteins in the interactome. Here, we studied these drugs further to identify whether any of them may potentially be repurposable for schizophrenia. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the drugs from the interactome using the BaseSpace Correlation Engine, and shortlisted those that had a negative correlation with differential gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes with opposite drug-induced versus schizophrenia-associated expression profiles were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had a pathophysiological overlap with schizophrenia. Drugs that targeted the same genes as the shortlisted drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis will help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development which faces a high failure rate.

| S-EPMC6722087 | biostudies-literature

Chinese Herbal Medicine Telehealth Outcomes for Symptoms Possibly Related to COVID-19

Project description: Not available

| S-EPMC8696086 | biostudies-literature