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1.
Front Endocrinol (Lausanne) ; 12: 802447, 2021.
Article in English | MEDLINE | ID: covidwho-1699427

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a serious epidemic, characterized by potential mutation and can bring about poor vaccine efficiency. It is evidenced that patients with malignancies, including prostate cancer (PC), may be highly vulnerable to the SARS-CoV-2 infection. Currently, there are no existing drugs that can cure PC and COVID-19. Luteolin can potentially be employed for COVID-19 treatment and serve as a potent anticancer agent. Our present study was conducted to discover the possible drug target and curative mechanism of luteolin to serve as treatment for PC and COVID-19. The differential gene expression of PC cases was determined via RNA sequencing. The application of network pharmacology and molecular docking aimed to exhibit the drug targets and pharmacological mechanisms of luteolin. In this study, we found the top 20 up- and downregulated gene expressions in PC patients. Enrichment data demonstrated anti-inflammatory effects, where improvement of metabolism and enhancement of immunity were the main functions and mechanism of luteolin in treating PC and COVID-19, characterized by associated signaling pathways. Additional core drug targets, including MPO and FOS genes, were computationally identified accordingly. In conclusion, luteolin may be a promising treatment for PC and COVID-19 based on bioinformatics findings, prior to future clinical validation and application.


Subject(s)
COVID-19/drug therapy , Drug Discovery/methods , Luteolin/therapeutic use , Prostatic Neoplasms/drug therapy , COVID-19/pathology , Computational Biology/methods , High-Throughput Screening Assays/methods , Humans , Luteolin/pharmacology , Male , Metabolic Networks and Pathways/drug effects , Models, Molecular , Molecular Docking Simulation , Molecular Targeted Therapy/methods , Prostatic Neoplasms/pathology , Protein Interaction Maps/drug effects , Protein Interaction Maps/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
2.
Mini Rev Med Chem ; 22(2): 273-311, 2022.
Article in English | MEDLINE | ID: covidwho-1666892

ABSTRACT

Due to the high mortality rate of the 2019 coronavirus disease (COVID-19) pandemic, there is an immediate need to discover drugs that can help before a vaccine becomes available. Given that the process of producing new drugs is so long, the strategy of repurposing existing drugs is one of the promising options for the urgent treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 disease. Although FDA has approved Remdesivir for the use in hospitalized adults and pediatric patients suffering from COVID-19, no fully effective and reliable drug has been yet identified worldwide to treat COVID-19 specifically. Thus, scientists are still trying to find antivirals specific to COVID-19. This work reviews the chemical structure, metabolic pathway, and mechanism of action of the existing drugs with potential therapeutic applications for COVID-19. Furthermore, we summarized the molecular docking stimulation of the medications related to key protein targets. These already established drugs could be further developed, and after their testing through clinical trials, they could be used as suitable therapeutic options for patients suffering from COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Metabolic Networks and Pathways/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Antiviral Agents/therapeutic use , Humans , Molecular Docking Simulation , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity
3.
Bioengineered ; 12(2): 12461-12469, 2021 12.
Article in English | MEDLINE | ID: covidwho-1585255

ABSTRACT

Severe mortality due to the COVID-19 pandemic resulted from the lack of effective treatment. Although COVID-19 vaccines are available, their side effects have become a challenge for clinical use in patients with chronic diseases, especially cancer patients. In the current report, we applied network pharmacology and systematic bioinformatics to explore the use of biochanin A in patients with colorectal cancer (CRC) and COVID-19 infection. Using the network pharmacology approach, we identified two clusters of genes involved in immune response (IL1A, IL2, and IL6R) and cell proliferation (CCND1, PPARG, and EGFR) mediated by biochanin A in CRC/COVID-19 condition. The functional analysis of these two gene clusters further illustrated the effects of biochanin A on interleukin-6 production and cytokine-cytokine receptor interaction in CRC/COVID-19 pathology. In addition, pathway analysis demonstrated the control of PI3K-Akt and JAK-STAT signaling pathways by biochanin A in the treatment of CRC/COVID-19. The findings of this study provide a therapeutic option for combination therapy against COVID-19 infection in CRC patients.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Colorectal Neoplasms/drug therapy , Gene Expression Regulation, Neoplastic/drug effects , Genistein/therapeutic use , Phytoestrogens/therapeutic use , Atlases as Topic , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/virology , Cyclin D1/genetics , Cyclin D1/immunology , ErbB Receptors/genetics , ErbB Receptors/immunology , Humans , Interleukin-1alpha/genetics , Interleukin-1alpha/immunology , Interleukin-2/genetics , Interleukin-2/immunology , Janus Kinases/genetics , Janus Kinases/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Molecular Targeted Therapy/methods , Multigene Family , PPAR gamma/genetics , PPAR gamma/immunology , Pharmacogenetics/methods , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/immunology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/immunology , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction
4.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
5.
Viruses ; 13(8)2021 08 04.
Article in English | MEDLINE | ID: covidwho-1359300

ABSTRACT

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.


Subject(s)
Antiviral Agents/therapeutic use , Dengue/drug therapy , Transcriptome , Adenosine Triphosphatases/antagonists & inhibitors , Adrenergic Antagonists/pharmacology , Adrenergic Antagonists/therapeutic use , Antiviral Agents/pharmacology , Brain/metabolism , Computer Simulation , Dengue/blood , Dengue/genetics , Dengue/metabolism , Drug Discovery , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Liver/metabolism , Metabolic Networks and Pathways/drug effects , NF-kappa B/metabolism , Serotonin Antagonists/pharmacology , Serotonin Antagonists/therapeutic use , Severe Dengue/blood , Severe Dengue/drug therapy , Severe Dengue/genetics , Severe Dengue/metabolism , Spleen/metabolism
6.
Bioorg Med Chem ; 46: 116356, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1347508

ABSTRACT

The ongoing COVID-19 pandemic, periodic recurrence of viral infections, and the emergence of challenging variants has created an urgent need of alternative therapeutic approaches to combat the spread of viral infections, failing to which may pose a greater risk to mankind in future. Resilience against antiviral drugs or fast evolutionary rate of viruses is stressing the scientific community to identify new therapeutic approaches for timely control of disease. Host metabolic pathways are exquisite reservoir of energy to viruses and contribute a diverse array of functions for successful replication and pathogenesis of virus. Targeting the host factors rather than viral enzymes to cease viral infection, has emerged as an alternative antiviral strategy. This approach offers advantage in terms of increased threshold to viral resistance and can provide broad-spectrum antiviral action against different viruses. The article here provides substantial review of literature illuminating the host factors and molecular mechanisms involved in innate/adaptive responses to viral infection, hijacking of signalling pathways by viruses and the intracellular metabolic pathways required for viral replication. Host-targeted drugs acting on the pathways usurped by viruses are also addressed in this study. Host-directed antiviral therapeutics might prove to be a rewarding approach in controlling the unprecedented spread of viral infection, however the probability of cellular side effects or cytotoxicity on host cell should not be ignored at the time of clinical investigations.


Subject(s)
Antiviral Agents/pharmacology , Positive-Strand RNA Viruses/drug effects , Animals , Cytokines/metabolism , Frameshifting, Ribosomal/drug effects , Frameshifting, Ribosomal/physiology , Glycosylation/drug effects , Humans , Immunity/drug effects , Immunity/physiology , Lipid Metabolism/drug effects , Lipid Metabolism/physiology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/physiology , Polyamines/metabolism , Positive-Strand RNA Viruses/physiology , Signal Transduction/drug effects , Signal Transduction/physiology , Ubiquitination/drug effects , Ubiquitination/physiology
7.
Mol Omics ; 17(3): 376-393, 2021 06 14.
Article in English | MEDLINE | ID: covidwho-1281750

ABSTRACT

Metabolomics has emerged as an invaluable tool that can be used along with genomics, transcriptomics and proteomics to understand host-pathogen interactions at small-molecule levels. Metabolomics has been used to study a variety of infectious diseases and applications. The most common application of metabolomics is for prognostic and diagnostic purposes, specifically the screening of disease-specific biomarkers by either NMR-based or mass spectrometry-based metabolomics. In addition, metabolomics is of great significance for the discovery of druggable metabolic enzymes and/or metabolic regulators through the use of state-of-the-art flux analysis, for example, via the elucidation of metabolic mechanisms. This review discusses the application of metabolomics technologies to biomarker screening, the discovery of drug targets in infectious diseases such as viral, bacterial and parasite infections and immunometabolomics, highlights the challenges associated with accessing metabolite compartmentalization and discusses the available tools for determining local metabolite concentrations.


Subject(s)
Biomarkers/metabolism , Communicable Diseases/metabolism , Metabolomics/methods , Communicable Diseases/drug therapy , Drug Discovery , Humans , Metabolic Networks and Pathways/drug effects , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use
8.
Cells ; 10(2)2021 02 21.
Article in English | MEDLINE | ID: covidwho-1110386

ABSTRACT

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent histone deacetylases that incorporate complex functions in the mechanisms of cell physiology. Mammals have seven distinct members of the SIRT family (SIRT1-7), which play an important role in a well-maintained network of metabolic pathways that control and adapt the cell to the environment, energy availability and cellular stress. Until recently, very few studies investigated the role of SIRTs in modulating viral infection and progeny. Recent studies have demonstrated that SIRT1 and SIRT2 are promising antiviral targets because of their specific connection to numerous metabolic and regulatory processes affected during infection. In the present review, we summarize some of the recent progress in SIRTs biochemistry and their emerging function as antiviral targets. We also discuss the potential of natural polyphenol-based SIRT modulators to control their functional roles in several diseases including viral infections.


Subject(s)
Metabolic Networks and Pathways , Sirtuins/metabolism , Virus Diseases/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Discovery , Humans , Metabolic Networks and Pathways/drug effects , Models, Molecular , Molecular Targeted Therapy , NAD/metabolism , Sirtuins/analysis , Virus Diseases/drug therapy , Viruses/drug effects , Viruses/metabolism
9.
Cell ; 184(1): 120-132.e14, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064914

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill defined. To address this gap, we performed genome-scale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E). These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, sterol regulatory element-binding protein (SREBP) signaling, bone morphogenetic protein (BMP) signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins. We identified an absolute requirement for the VMP1, TMEM41, and TMEM64 (VTT) domain-containing protein transmembrane protein 41B (TMEM41B) for infection by SARS-CoV-2 and three seasonal coronaviruses. This human coronavirus host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus pandemics.


Subject(s)
Coronavirus Infections/genetics , Genome-Wide Association Study , SARS-CoV-2/physiology , A549 Cells , Cell Line , Clustered Regularly Interspaced Short Palindromic Repeats , Coronavirus 229E, Human/physiology , Coronavirus Infections/virology , Coronavirus NL63, Human/physiology , Coronavirus OC43, Human/physiology , Gene Knockout Techniques , HEK293 Cells , Host-Pathogen Interactions/drug effects , Humans , Membrane Proteins/metabolism , Metabolic Networks and Pathways/drug effects , Protein Interaction Mapping
10.
Commun Biol ; 3(1): 466, 2020 08 18.
Article in English | MEDLINE | ID: covidwho-723561

ABSTRACT

Chinese herbal formulas including the lung-cleaning and toxicity-excluding (LCTE) soup have played an important role in treating the ongoing COVID-19 pandemic (caused by SARS-CoV-2) in China. Applying LCTE outside of China may prove challenging due to the unfamiliar rationale behind its application in terms of Traditional Chinese Medicine. To overcome this barrier, a biochemical understanding of the clinical effects of LCTE is needed. Here, we explore the chemical compounds present in the reported LCTE ingredients and the proteins targeted by these compounds via a network pharmacology analysis. Our results indicate that LCTE contains compounds with the potential to directly inhibit SARS-CoV-2 and inflammation, and that the compound targets proteins highly related to COVID-19's main symptoms. We predict the general effect of LCTE is to affect the pathways involved in viral and other microbial infections, inflammation/cytokine response, and lung diseases. Our work provides a biochemical basis for using LCTE to treat COVID-19 and its main symptoms.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Medicine, Chinese Traditional , Pandemics , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19 , Calcium Sulfate , China/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Drug Delivery Systems , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Gastrointestinal Tract/drug effects , Humans , Metabolic Networks and Pathways/drug effects , Phytotherapy , Plants, Medicinal/chemistry , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Respiratory System/drug effects , SARS-CoV-2 , Viral Proteins/antagonists & inhibitors
11.
J Cell Biol ; 219(10)2020 10 05.
Article in English | MEDLINE | ID: covidwho-713813

ABSTRACT

With the rapid global spread of SARS-CoV-2, we have become acutely aware of the inadequacies of our ability to respond to viral epidemics. Although disrupting the viral life cycle is critical for limiting viral spread and disease, it has proven challenging to develop targeted and selective therapeutics. Synthetic lethality offers a promising but largely unexploited strategy against infectious viral disease; as viruses infect cells, they abnormally alter the cell state, unwittingly exposing new vulnerabilities in the infected cell. Therefore, we propose that effective therapies can be developed to selectively target the virally reconfigured host cell networks that accompany altered cellular states to cripple the host cell that has been converted into a virus factory, thus disrupting the viral life cycle.


Subject(s)
Antiviral Agents/pharmacology , Host Microbial Interactions/drug effects , Virus Diseases/drug therapy , Virus Replication/drug effects , Drug Discovery , Humans , Immunologic Factors/pharmacology , Metabolic Networks and Pathways/drug effects , Protein Interaction Maps , Proteolysis , RNA Viruses/drug effects , RNA Viruses/physiology , Virus Diseases/genetics
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