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1.
Mol Cell Biochem ; 477(3): 711-726, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1616202

ABSTRACT

The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.


Subject(s)
Antiviral Agents/immunology , COVID-19/drug therapy , /pharmacology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antiviral Agents/pharmacology , Azetidines/immunology , Azetidines/pharmacology , COVID-19/etiology , Dexamethasone/immunology , Dexamethasone/pharmacology , Famotidine/immunology , Famotidine/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/immunology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Infliximab/immunology , Infliximab/pharmacology , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Melatonin/immunology , Melatonin/pharmacology , Purines/immunology , Purines/pharmacology , Pyrazoles/immunology , Pyrazoles/pharmacology , Sulfonamides/immunology , Sulfonamides/pharmacology
2.
Int Immunopharmacol ; 103: 108463, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1587490

ABSTRACT

Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1ß and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.


Subject(s)
Concanavalin A/toxicity , Cytokine Release Syndrome/chemically induced , Cytokine Release Syndrome/drug therapy , Nitriles/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Aldehydes/metabolism , Animals , Chemical and Drug Induced Liver Injury , Dose-Response Relationship, Drug , Inflammation/chemically induced , Liver/drug effects , Liver/metabolism , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred BALB C , Nitrates/metabolism , Nitriles/administration & dosage , Nitrites/metabolism , Oxidative Stress , Peroxidase/metabolism , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage
3.
Virology ; 566: 60-68, 2022 01.
Article in English | MEDLINE | ID: covidwho-1537115

ABSTRACT

The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but effective antiviral therapies are not widely available. To improve treatment options, we conducted a high-throughput screen to uncover compounds that block SARS-CoV-2 infection. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed across 10 dose points. Our screening revealed several FDA-approved agents that can attenuate both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 RNA replication by over 50,000-fold. Further, both lapatinib and doramapimod could be combined with remdesivir to improve antiviral activity in cells. These findings reveal novel therapeutic avenues that could limit SARS-CoV-2 infection.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/drug therapy , Lapatinib/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Animals , Benzoquinones/pharmacology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Drug Combinations , Drug Discovery , Drug Synergism , High-Throughput Screening Assays , Humans , Lactams, Macrocyclic/pharmacology , Naphthalenes/pharmacology , Phenylurea Compounds/pharmacology , Pyrazoles/pharmacology , RNA, Viral/metabolism , Vero Cells , Virus Replication/drug effects
4.
Chem Commun (Camb) ; 57(93): 12476-12479, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1500757

ABSTRACT

We identified small-molecule enhancers of cellular stress granules by observing molecular crowding of proteins and RNAs in a time-dependent manner. Hit molecules sensitized the IRF3-mediated antiviral mechanism in the presence of poly(I:C) and inhibited the replication of SARS-CoV-2 by inducing stress granule formation. Thus, modulating multimolecular crowding can be a promising strategy against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Benzopyrans/pharmacology , Cytoplasmic Granules/drug effects , Pyrazoles/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Benzopyrans/chemistry , Cell Line, Tumor , Chlorocebus aethiops , Cytoplasmic Granules/metabolism , Dose-Response Relationship, Drug , Drug Combinations , Humans , Interferon Regulatory Factor-3/metabolism , Lopinavir/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Poly I-C/pharmacology , Pyrazoles/chemistry , Structure-Activity Relationship , Vero Cells
5.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432

ABSTRACT

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.


Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects
6.
Molecules ; 25(19)2020 Oct 06.
Article in English | MEDLINE | ID: covidwho-1389458

ABSTRACT

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (-8.1 ± 0.33 kcal/mol, -8.0 ± 0.35 kcal/mol, and -8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (-6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.


Subject(s)
Antiviral Agents/chemical synthesis , Betacoronavirus/enzymology , Hydrazones/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , Pyrazoles/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Discovery , Humans , Hydrazones/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrazines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2 , Thermodynamics , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
8.
Mol Syst Biol ; 17(9): e10426, 2021 09.
Article in English | MEDLINE | ID: covidwho-1355289

ABSTRACT

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Cytokines/metabolism , Host-Pathogen Interactions/physiology , Animals , Azetidines/pharmacology , Host-Pathogen Interactions/drug effects , Humans , Imidazoles/pharmacology , Interleukin-1 Receptor-Associated Kinases/metabolism , Janus Kinase 1/metabolism , Lipopolysaccharides/toxicity , Machine Learning , Male , Mice , Mice, Inbred C57BL , Neutrophils/virology , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Pyrazoles/pharmacology , Pyridazines/pharmacology , RAW 264.7 Cells , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Sulfonamides/pharmacology
9.
Biomolecules ; 11(7)2021 07 16.
Article in English | MEDLINE | ID: covidwho-1323103

ABSTRACT

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Subject(s)
Antineoplastic Agents/therapeutic use , Celecoxib/therapeutic use , Cyclooxygenase 2 Inhibitors/therapeutic use , Neoplasms/drug therapy , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Celecoxib/adverse effects , Celecoxib/analogs & derivatives , Celecoxib/pharmacology , Cell Cycle/drug effects , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Humans , Pyrazoles/adverse effects , Pyrazoles/chemistry , Pyrazoles/pharmacology , Sulfonamides/adverse effects , Sulfonamides/chemistry , Sulfonamides/pharmacology
10.
Sci Rep ; 11(1): 10763, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1242041

ABSTRACT

Research on drugs against SARS-CoV-2 (cause of COVID-19) has been one of the major world concerns at present. There have been abundant research data and findings in this field. The interference of drugs on gene expression in cell lines, drug-target, protein-virus receptor networks, and immune cell infiltration of the host may provide useful information for anti-SARS-CoV-2 drug research. To simplify the complex bioinformatics analysis and facilitate the evaluation of the latest research data, we developed OmiczViz ( http://medcode.link/omicsviz ), a web tool that has integrated drug-cell line interference data, virus-host protein-protein interactions, and drug-target interactions. To demonstrate the usages of OmiczViz, we analyzed the gene expression data from cell lines treated with chloroquine and ruxolitinib, the drug-target protein networks of 48 anti-coronavirus drugs and drugs bound with ACE2, and the profiles of immune cell infiltration between different COVID-19 patient groups. Our research shows that chloroquine had a regulatory role of the immune response in renal cell line but not in lung cell line. The anti-coronavirus drug-target network analysis suggested that antihistamine of promethaziney and dietary supplement of Zinc might be beneficial when used jointly with antiviral drugs. The immune infiltration analysis indicated that both the COVID-19 patients admitted to the ICU and the elderly with infection showed immune exhaustion status, yet with different molecular mechanisms. The interactive graphic interface of OmiczViz also makes it easier to analyze newly discovered and user-uploaded data, leading to an in-depth understanding of existing findings and an expansion of existing knowledge of SARS-CoV-2. Collectively, OmicsViz is web program that promotes the research on medical agents against SARS-CoV-2 and supports the evaluation of the latest research findings.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , User-Computer Interface , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Cell Line , Chloroquine/pharmacology , Gene Expression Regulation/drug effects , Humans , Internet , Nitriles , Protein Binding , Pyrazoles/pharmacology , Pyrimidines , Severity of Illness Index
11.
J Hepatol ; 75(3): 647-658, 2021 09.
Article in English | MEDLINE | ID: covidwho-1228069

ABSTRACT

BACKGROUND AND AIMS: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. METHODS: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. RESULTS: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. CONCLUSION: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.


Subject(s)
COVID-19/complications , Endothelial Cells/pathology , Interleukin-6/physiology , Liver Diseases/etiology , SARS-CoV-2 , Adult , Blood Coagulation Disorders/etiology , Fibrinogen/analysis , Humans , Interleukin-6/blood , Janus Kinase 1/metabolism , Nitriles , Pyrazoles/pharmacology , Pyrimidines , Retrospective Studies , STAT3 Transcription Factor/metabolism , Signal Transduction/physiology , von Willebrand Factor/analysis
12.
J Clin Pharmacol ; 61(10): 1274-1285, 2021 10.
Article in English | MEDLINE | ID: covidwho-1192122

ABSTRACT

Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon-mediated autoinflammatory diseases, graft-versus-host disease, diabetic kidney disease, and, recently, coronavirus disease-19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib-treated patients, ranging from simple infections to increased risk of malignancies, particularly in long-term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Azetidines/pharmacology , COVID-19 , Inflammation/drug therapy , Purines/pharmacology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Humans , Janus Kinase Inhibitors/pharmacology , Risk Assessment , SARS-CoV-2 , Treatment Outcome
13.
Mol Ther ; 29(3): 1174-1185, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-985497

ABSTRACT

Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC50) by ∼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.


Subject(s)
Immunity, Innate/drug effects , Immunogenicity, Vaccine , Protein Biosynthesis/drug effects , Vaccines, Synthetic/pharmacology , Viral Envelope Proteins/administration & dosage , Animals , Cell Line , Encephalitis Virus, Venezuelan Equine/drug effects , Encephalitis Virus, Venezuelan Equine/immunology , Encephalitis Virus, Venezuelan Equine/pathogenicity , Fibroblasts , Gene Expression Regulation , HeLa Cells , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunoglobulin G/biosynthesis , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/immunology , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/immunology , Mice , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , NF-kappa B/genetics , NF-kappa B/immunology , Nitriles , Parainfluenza Virus 5/drug effects , Parainfluenza Virus 5/immunology , Parainfluenza Virus 5/pathogenicity , Pyrazoles/pharmacology , Pyrimidines , Rabbits , Rabies virus/drug effects , Rabies virus/immunology , Rabies virus/pathogenicity , Rats , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction , Vaccines, Synthetic/biosynthesis , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology
14.
PLoS Pathog ; 17(2): e1009371, 2021 02.
Article in English | MEDLINE | ID: covidwho-1138592

ABSTRACT

Morbilliviruses, such as measles virus (MeV) and canine distemper virus (CDV), are highly infectious members of the paramyxovirus family. MeV is responsible for major morbidity and mortality in non-vaccinated populations. ERDRP-0519, a pan-morbillivirus small molecule inhibitor for the treatment of measles, targets the morbillivirus RNA-dependent RNA-polymerase (RdRP) complex and displayed unparalleled oral efficacy against lethal infection of ferrets with CDV, an established surrogate model for human measles. Resistance profiling identified the L subunit of the RdRP, which harbors all enzymatic activity of the polymerase complex, as the molecular target of inhibition. Here, we examined binding characteristics, physical docking site, and the molecular mechanism of action of ERDRP-0519 through label-free biolayer interferometry, photoaffinity cross-linking, and in vitro RdRP assays using purified MeV RdRP complexes and synthetic templates. Results demonstrate that unlike all other mononegavirus small molecule inhibitors identified to date, ERDRP-0519 inhibits all phosphodiester bond formation in both de novo initiation of RNA synthesis at the promoter and RNA elongation by a committed polymerase complex. Photocrosslinking and resistance profiling-informed ligand docking revealed that this unprecedented mechanism of action of ERDRP-0519 is due to simultaneous engagement of the L protein polyribonucleotidyl transferase (PRNTase)-like domain and the flexible intrusion loop by the compound, pharmacologically locking the polymerase in pre-initiation conformation. This study informs selection of ERDRP-0519 as clinical candidate for measles therapy and identifies a previously unrecognized druggable site in mononegavirus L polymerase proteins that can silence all synthesis of viral RNA.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Measles virus/drug effects , Measles/drug therapy , Morpholines/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , RNA, Viral/biosynthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Chlorocebus aethiops , Measles/metabolism , Measles/virology , Measles virus/enzymology , Mutation , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Vero Cells
15.
Sci Rep ; 11(1): 2512, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1054059

ABSTRACT

Whenever some phenomenon can be represented as a graph or a network it seems pertinent to explore how much the mathematical properties of that network impact the phenomenon. In this study we explore the same philosophy in the context of immunology. Our objective was to assess the correlation of "size" (number of edges and minimum vertex cover) of the JAK/STAT network with treatment effect in rheumatoid arthritis (RA), phenotype of viral infection and effect of immunosuppressive agents on a system infected with the coronavirus. We extracted the JAK/STAT pathway from Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04630). The effects of the following drugs, and their combinations, commonly used in RA were tested: methotrexate, prednisolone, rituximab, tocilizumab, tofacitinib and baricitinib. Following viral systems were also tested for their ability to evade the JAK/STAT pathway: Measles, Influenza A, West Nile virus, Japanese B virus, Yellow Fever virus, respiratory syncytial virus, Kaposi's sarcoma virus, Hepatitis B and C virus, cytomegalovirus, Hendra and Nipah virus and Coronavirus. Good correlation of edges and minimum vertex cover with clinical efficacy were observed (for edge, rho = - 0.815, R2 = 0.676, p = 0.007, for vertex cover rho = - 0.793, R2 = 0.635, p = 0.011). In the viral systems both edges and vertex cover were associated with acuteness of viral infections. In the JAK/STAT system already infected with coronavirus, maximum reduction in size was achieved with baricitinib. To conclude, algebraic and combinatorial invariant of a network may explain its biological behaviour. At least theoretically, baricitinib may be an attractive target for treatment of coronavirus infection.


Subject(s)
Arthritis, Rheumatoid/metabolism , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Virus Diseases/drug therapy , Virus Diseases/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/genetics , Azetidines/pharmacology , Gene Regulatory Networks , Humans , Janus Kinases/genetics , Methotrexate/pharmacology , Models, Statistical , Piperidines/pharmacology , Prednisolone/pharmacology , Purines/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Rituximab/pharmacology , STAT Transcription Factors/genetics , Signal Transduction/drug effects , Sulfonamides/pharmacology
17.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1030457

ABSTRACT

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , Chloroquine/pharmacology , Chloroquine/therapeutic use , Drug Combinations , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Immunization, Passive , Indoles/pharmacology , Indoles/therapeutic use , Interferons/pharmacology , Interferons/therapeutic use , Ivermectin/pharmacology , Ivermectin/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Nitro Compounds , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Purines/pharmacology , Purines/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thiazoles/pharmacology , Thiazoles/therapeutic use
18.
Infect Genet Evol ; 85: 104419, 2020 11.
Article in English | MEDLINE | ID: covidwho-997272

ABSTRACT

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Benzoates/pharmacology , Hydrazines/pharmacology , Pyrazoles/pharmacology , SARS Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Algorithms , Angiotensin-Converting Enzyme 2/chemistry , Benzoates/chemistry , Computer Simulation , Drug Design , Drug Repositioning , Humans , Hydrazines/chemistry , Models, Molecular , Protein Binding , Protein Stability , Pyrazoles/chemistry , SARS Virus/drug effects , SARS-CoV-2/drug effects , Structure-Activity Relationship
19.
J Mol Graph Model ; 102: 107763, 2021 01.
Article in English | MEDLINE | ID: covidwho-974283

ABSTRACT

The molecular electronic density theory (MEDT) was invested to elucidate the chemo-, regio- and stereo-selectivity of the 1,3-dipolar cycloaddition between Diazomethane (DZM) and Psilostachyin (PSH). The DFT method at B3LYP/6-31 + G (d,p) level of theory was used. Reactivity indices, transition structures theory, IGM and ELF analysis were employed to reveal the mechanism of the reaction. The addition of DZM to PSH takes place through a one-step mechanism and an asynchronous transition states. Eight possible addition channels of reaction were investigated (addition of C (sp2) to Diazomethane at C4, C5, C6 or C7). The addition of C (sp2) at C5 leading to P1 product is the preferred channel. The addition of ether does not affect the chemo-, regio- and stereo-selectivity of the reaction. Analysis of transfer of charges along the IRC path associated with the P1 product shows a polar character for the studied reaction. We have also used the noncovalent interaction (NCI) which is very helpful to reveal the most favored addition channel of the reaction, by analyzing the weak interactions in different TSs. Finally, we investigate about the potential of inhibition of some pyrazoline compounds against COVID-19-Mpro by performing a molecular docking calculations.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Lactones/chemistry , Lactones/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/drug effects , COVID-19/drug therapy , COVID-19/virology , Cycloaddition Reaction , Diazomethane/chemistry , Humans , Molecular Docking Simulation , Pandemics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Conformation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Static Electricity
20.
Theranostics ; 11(1): 316-329, 2021.
Article in English | MEDLINE | ID: covidwho-922935

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Immunosuppressive Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokines/antagonists & inhibitors , Cytokines/immunology , Humans , Immunosuppressive Agents/pharmacology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , SARS-CoV-2/immunology , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/metabolism , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment Outcome
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