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1.
Mol Med ; 28(1): 27, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1724403

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.


Subject(s)
Acute Lung Injury/drug therapy , COVID-19/drug therapy , Hydrogen/pharmacology , Protective Agents/pharmacology , Acute Lung Injury/physiopathology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Humans , Sepsis/drug therapy , Sepsis/physiopathology
2.
Pharmacol Res Perspect ; 10(2): e00940, 2022 04.
Article in English | MEDLINE | ID: covidwho-1712175

ABSTRACT

Anti-proinflammatory cytokine therapies against interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), a simple monosaccharide, attenuated cellular responses to IL-6 by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglycoforms of gp130 did not bind to IL-6 or activate downstream intracellular signals that included Janus kinases. 2-DG completely inhibited dextran sodium sulfate-induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin-induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL-6. We also found that 2-DG inhibited signals for other proinflammatory cytokines such as TNF-α, IL-1ß, and interferon -γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2-DG prevented LPS shock, a model for a cytokine storm, and LPS-induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID-19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Deoxyglucose/pharmacology , Glycosylation/drug effects , Inflammation/prevention & control , Receptors, Cytokine/drug effects , Animals , Cells, Cultured , Cytokine Receptor gp130/antagonists & inhibitors , Cytokine Receptor gp130/metabolism , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Inflammation/chemically induced , Janus Kinases/drug effects , Lipopolysaccharides , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Cytokine/immunology , Receptors, Cytokine/metabolism , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/metabolism
3.
Int J Mol Sci ; 23(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1703931

ABSTRACT

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Selenium Compounds/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/chemistry , Humans , Immune System/drug effects , Organoselenium Compounds/immunology , Organoselenium Compounds/pharmacokinetics , Organoselenium Compounds/pharmacology , Selenium Compounds/immunology , Selenocysteine/analogs & derivatives , Selenocysteine/immunology , Selenocysteine/pharmacology , Selenomethionine/pharmacokinetics , Selenomethionine/pharmacology , Sodium Selenite/pharmacology
4.
Int J Mol Sci ; 23(3)2022 Jan 19.
Article in English | MEDLINE | ID: covidwho-1625123

ABSTRACT

SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications-including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)-have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.


Subject(s)
Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/genetics , Acetaminophen/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Caco-2 Cells , Disease Progression , Enzyme Activation/drug effects , Etoricoxib/pharmacology , Flurbiprofen/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Humans , Ibuprofen/pharmacology , Male , Mice , Mice, Inbred C57BL , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Internalization/drug effects
5.
Bioorg Chem ; 119: 105550, 2022 02.
Article in English | MEDLINE | ID: covidwho-1561636

ABSTRACT

Infectious diseases caused by new or unknown bacteria and viruses, such as anthrax, cholera, tuberculosis and even COVID-19, are a major threat to humanity. Thus, the development of new synthetic compounds with efficient antimicrobial activity is a necessity. Herein, rationally designed novel multifunctional cationic alternating copolymers were directly synthesized through a step-growth polymerization reaction using a bivalent electrophilic cross-linker containing disulfide bonds and a diamine heterocyclic ring. To optimize the activity of these alternating copolymers, several different diamines and cross-linkers were explored to find the highest antibacterial effects. The synthesized nanopolymers not only displayed good to excellent antibacterial activity as judged by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Escherichia coli, but also reduced the number of biofilm cells even at low concentrations, without killing mammalian cells. Furthermore, in vivo experiments using infected burn wounds in mice demonstrated good antibacterial activity and stimulated wound healing, without causing systemic inflammation. These findings suggest that the multifunctional cationic nanopolymers have potential as a novel antibacterial agent for eradication of multidrug resistant bacterial infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biofilms/drug effects , Cations/pharmacology , Polymers/pharmacology , Wound Healing/drug effects , Amines/chemistry , Animals , Bacteria/drug effects , Bacterial Infections/drug therapy , Bacterial Infections/etiology , Burns/complications , COVID-19 , Cell Survival/drug effects , Cross-Linking Reagents , Drug Resistance, Multiple, Bacterial/drug effects , HEK293 Cells/drug effects , Humans , Mice , Microbial Sensitivity Tests , Polymers/chemistry
6.
Inflammopharmacology ; 30(1): 343-348, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1530348

ABSTRACT

We have previously published several papers illustrating numerous immunomodulatory and anti-inflammatory potential benefits when we repurposed safe, generic non-steroidal anti-inflammatory drugs (NSAIDs)/nitazoxanide/azithromycin (Kelleni's protocol), to early manage our COVID-19 pediatric, adult, and pregnant patients. In this manuscript, we discuss some recently published meta-analysis and clinical studies supporting our practice and discuss a molecular study that might be interpreted as an academic proof that our protocol might also prevent SARS-CoV-2 replication. Moreover, after aspirin has been suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19, we claim that the molecular interpretation of the results that led to this suggestion was not scientifically accurate, and we provide our academic interpretation confirming that low-dose aspirin is least likely to improve COVID-19 mortality through anticoagulation as was suggested. Furthermore, we describe other potential benefits related to aspirin-triggered lipoxins and resolvins while illustrating how NSAIDs interfere with COX-1, COX-2, SARS-CoV-2/ SARS-CoV-2 ORF protein-dependent activation of caspases and their subsequent mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis and necroptosis which were associated with COVID-19 complications. Similarly, NSAIDs are known caspase inhibitors and thus they might independently inhibit other caspase-related COVID-19-associated downstream pathological signaling mechanisms. Finally, we postulated that CARD-14, a caspase recruitment domain-containing protein, polymorphisms might play a role in the development of severe and critical COVID-19 and confirmed our old call to early adopt NSAIDs, as an integral part of Kelleni's protocol, as of choice in its management aiming to end this pandemic.


Subject(s)
COVID-19 , Adult , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19/drug therapy , Child , Humans , Pandemics , SARS-CoV-2
7.
Eur J Med Chem ; 229: 114002, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1517139

ABSTRACT

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Autoimmune Diseases/drug therapy , Caspase 1/drug effects , Inflammasomes/drug effects , Inflammation/drug therapy , Serpins/chemical synthesis , Serpins/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/therapeutic use , Viral Proteins/chemical synthesis , Viral Proteins/pharmacology , COVID-19 , Cell Division/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Interleukin-1beta/metabolism , Macrophages/drug effects , Macrophages/metabolism , Tetrazoles/pharmacology , U937 Cells
8.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1478110

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
9.
Molecules ; 26(19)2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1438673

ABSTRACT

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Esters/chemistry , Esters/pharmacology , Halogenation , Humans , Ibuprofen/analogs & derivatives , Ibuprofen/pharmacology , Indomethacin/analogs & derivatives , Indomethacin/pharmacology , Molecular Docking Simulation , Pyridines/chemistry , Pyridines/pharmacology , SARS-CoV-2/metabolism , Salicylic Acid/chemistry , Salicylic Acid/pharmacology , Vero Cells
10.
Bioorg Chem ; 116: 105346, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401246

ABSTRACT

Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1ß and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.


Subject(s)
Amines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Chloroquine/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amines/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , B-Lymphocytes/immunology , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Cytokines/metabolism , Dose-Response Relationship, Drug , Humans , Macrophages/drug effects , Macrophages/immunology , Microbial Sensitivity Tests , Molecular Structure , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
11.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1390793

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
12.
Bioorg Chem ; 116: 105272, 2021 11.
Article in English | MEDLINE | ID: covidwho-1370451

ABSTRACT

Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2:SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antihypertensive Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Calcium Channel Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Humans , SARS-CoV-2/drug effects
13.
Arch Pharm (Weinheim) ; 354(11): e2100160, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1370365

ABSTRACT

Boswellic acids (BAs) have been shown to possess antiviral activity. Using bioinformatic methods, it was tested whether or not acetyl-11-keto-ß-boswellic acid (AKBA), 11-keto-ß-boswellic acid (KBA), ß-boswellic acid (BBA), and the phosphorylated active metabolite of Remdesivir® (RGS-P3) bind to functional proteins of SARS-CoV-2, that is, the replicase polyprotein P0DTD1, the spike glycoprotein P0DTC2, and the nucleoprotein P0DTC9. Using P0DTD1, AKBA and KBA showed micromolar binding affinity to the RNA-dependent RNA polymerase (RdRp) and to the main proteinase complex Mpro . Phosphorylated BAs even bond in the nanomolar range. Due to their positive and negative charges, BAs and RGS-P3 bond to corresponding negative and positive areas of the protein. BAs and RGS-P3 docked in the tunnel-like cavity of RdRp. BAs also docked into the elongated surface rim of viral Mpro . In both cases, binding occurred with active site amino acids in the lower micromolecular to upper nanomolar range. KBA, BBA, and RGS-P3 also bond to P0DTC2 and P0DTC9. The binding energies for BAs were in the range of -5.8 to -6.3 kcal/mol. RGS-P3 and BAs occluded the centrally located pore of the donut-like protein structure of P0DTC9 and, in the case of P0DTC2, RGS-P3 and BAs impacted the double-wing-like protein structure. The data of this bioinformatics study clearly show that BAs bind to three functional proteins of the SARS-CoV-2 virus responsible for adhesion and replication, as does RGS-P3, a drug on the market to treat this disease. The binding effectiveness of BAs can be increased through phosphate esterification. Whether or not BAs are druggable against the SARS-CoV-2 disease remains to be established.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/physiology , Triterpenes/pharmacology , Viral Proteins/physiology , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Binding Sites/physiology , Boswellia , COVID-19/drug therapy , COVID-19/virology , Computational Biology/methods , Humans , Molecular Docking Simulation , Nucleoproteins/metabolism , Polyproteins/metabolism , Prodrugs/pharmacology , Protein Binding/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Structure-Activity Relationship
14.
Bioorg Chem ; 116: 105274, 2021 11.
Article in English | MEDLINE | ID: covidwho-1363884

ABSTRACT

Traditional Chinese herbal compound prescription in Xuanfei Baidu Tang (XBT) has obvious effects in the treatment of COVID-19. However, its effective compounds and targets for the treatment of COVID-19 remain unclear. Computer-Aided Drug Design is used to virtually screen out the anti-inflammatory or anti-viral compounds in XBT, and predict the potential targets by Discovery Studio 2020. Then, we searched for COVID-19 targets using Genecards databases and Protein Data Bank (PDB) databases and compared them to identify targets that were common to both. Finally, the target we screened out is: TP53 (Tumor Protein P53). This article also shows that XBT in the treatment of COVID-19 works in a multi-link and overall synergistic manner. Our results will help to design the new drugs for COVID-19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemistry , Drug Evaluation, Preclinical , Drugs, Chinese Herbal/chemistry , Humans , Medicine, Chinese Traditional , Molecular Structure , SARS-CoV-2/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism
15.
Mol Syst Biol ; 17(8): e10239, 2021 08.
Article in English | MEDLINE | ID: covidwho-1335457

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Evaluation, Preclinical/methods , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/genetics , COVID-19/virology , Chlorocebus aethiops , Drug Repositioning , HEK293 Cells , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/physiology , Humans , Imidazoles/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Salmeterol Xinafoate/pharmacology , Vero Cells
16.
Comput Biol Med ; 136: 104686, 2021 09.
Article in English | MEDLINE | ID: covidwho-1330715

ABSTRACT

The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (-6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Antiviral Agents/pharmacology , COVID-19 , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arachidonic Acid , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases , Protease Inhibitors/pharmacology , SARS-CoV-2
17.
Biomed Pharmacother ; 141: 111888, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1293595

ABSTRACT

Curcumin, isolated from Curcuma longa L., is a fat-soluble natural compound that can be obtained from ginger plant tuber roots, which accumulative evidences have demonstrated that it can resist viral and microbial infection and has anti-tumor, reduction of blood lipid and blood glucose, antioxidant and removal of free radicals, and is active against numerous disorders various chronic diseases including cardiovascular, pulmonary, neurological and autoimmune diseases. In this article is highlighted the recent evidence of curcuminoids applied in sevral aspects of medical problem particular in COVID-19 pandemics. We have searched several literature databases including MEDLINE (PubMed), EMBASE, the Web of Science, Cochrane Library, Google Scholar, and the ClinicalTrials.gov website via using curcumin and medicinal properties as a keyword. All studies published from the time when the database was established to May 2021 was retrieved. This review article summarizes the growing confirmation for the mechanisms related to curcumin's physiological and pharmacological effects with related target proteins interaction via molecular docking. The purpose is to provide deeper insight and understandings of curcumin's medicinal value in the discovery and development of new drugs. Curcumin could be used in the prevention or therapy of cardiovascular disease, respiratory diseases, cancer, neurodegeneration, infection, and inflammation based on cellular biochemical, physiological regulation, infection suppression and immunomodulation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antineoplastic Agents/therapeutic use , Antioxidants/therapeutic use , Curcumin/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/metabolism , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Curcumin/metabolism , Curcumin/pharmacology , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Structure, Secondary
18.
J Nutr Biochem ; 97: 108787, 2021 11.
Article in English | MEDLINE | ID: covidwho-1253236

ABSTRACT

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/therapeutic use , COVID-19/therapy , Dietary Supplements , Gastrointestinal Microbiome , Phenols/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/pharmacokinetics , Antioxidants/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biological Availability , Curcumin/pharmacokinetics , Curcumin/pharmacology , Curcumin/therapeutic use , Dietary Supplements/analysis , Gastrointestinal Microbiome/drug effects , Humans , Immunologic Factors/pharmacokinetics , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Phenols/pharmacokinetics , Phenols/pharmacology , Quercetin/pharmacokinetics , Quercetin/pharmacology , Quercetin/therapeutic use , Resveratrol/pharmacokinetics , Resveratrol/pharmacology , Resveratrol/therapeutic use , SARS-CoV-2/drug effects
19.
Sci Rep ; 11(1): 9606, 2021 05 05.
Article in English | MEDLINE | ID: covidwho-1217709

ABSTRACT

Non-steroidal anti-inflammatory drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 (Coronavirus disease 2019) patients as potent painkillers and anti-inflammatory agents. However, the prospective anti-COVID-19 mechanisms of NSAIDs are not evidently exposed. Therefore, we intended to decipher the most influential NSAIDs candidate(s) and its novel mechanism(s) against COVID-19 by network pharmacology. FDA (U.S. Food & Drug Administration) approved NSAIDs (19 active drugs and one prodrug) were used for this study. Target proteins related to selected NSAIDs and COVID-19 related target proteins were identified by the Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases, respectively. Venn diagram identified overlapping target proteins between NSAIDs and COVID-19 related target proteins. The interactive networking between NSAIDs and overlapping target proteins was analyzed by STRING. RStudio plotted the bubble chart of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis of overlapping target proteins. Finally, the binding affinity of NSAIDs against target proteins was determined through molecular docking test (MDT). Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19. Inhibition of proinflammatory stimuli of tissues and/or cells by inactivating the RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. Besides, MAPK8, MAPK10, and BAD target proteins were explored as the associated target proteins of the RAS. Among twenty NSAIDs, 6MNA, Rofecoxib, and Indomethacin revealed promising binding affinity with the highest docking score against three identified target proteins, respectively. Overall, our proposed three NSAIDs (6MNA, Rofecoxib, and Indomethacin) might block the RAS by inactivating its associated target proteins, thus may alleviate excessive inflammation induced by SARS-CoV-2.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical/methods , Proteins/metabolism , SARS-CoV-2/drug effects , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antiviral Agents/metabolism , Humans , Mitogen-Activated Protein Kinase 10/chemistry , Mitogen-Activated Protein Kinase 10/metabolism , Mitogen-Activated Protein Kinase 8/chemistry , Mitogen-Activated Protein Kinase 8/metabolism , Molecular Targeted Therapy , Protein Interaction Maps/drug effects , SARS-CoV-2/metabolism , Signal Transduction/drug effects , bcl-Associated Death Protein/chemistry , bcl-Associated Death Protein/metabolism , ras Proteins/metabolism
20.
Molecules ; 26(9)2021 Apr 29.
Article in English | MEDLINE | ID: covidwho-1217101

ABSTRACT

There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could be a strategy to impede viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that was previously demonstrated to be active against Influenza A virus, were evaluated against SARS-CoV-2. Intrinsic fluorescence spectroscopy, fluorescence anisotropy, and dynamic light scattering assays demonstrated naproxen binding to the nucleoprotein of SARS-Cov-2 as predicted by molecular modeling. Naproxen impeded recombinant N oligomerization and inhibited viral replication in infected cells. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage. No inhibition of viral replication was observed with paracetamol or the COX-2 inhibitor celecoxib. Thus, among the NSAID tested, only naproxen combined antiviral and anti-inflammatory properties. Naproxen addition to the standard of care could be beneficial in a clinical setting, as tested in an ongoing clinical study.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Naproxen/pharmacology , Nucleoproteins/antagonists & inhibitors , SARS-CoV-2/drug effects , Viral Proteins/antagonists & inhibitors , Animals , Cell Line , Chlorocebus aethiops , Drug Repositioning , Humans , Molecular Docking Simulation , Nucleoproteins/metabolism , SARS-CoV-2/physiology , Vero Cells , Viral Proteins/metabolism , Virus Replication/drug effects
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