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1.
J Med Chem ; 64(24): 18010-18024, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1616926

ABSTRACT

Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.


Subject(s)
Antiviral Agents/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Imino Sugars/pharmacology , Inositol/analogs & derivatives , alpha-Glucosidases/metabolism , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Chlorocebus aethiops , Crystallography, X-Ray , Dengue Virus/drug effects , Endoplasmic Reticulum/enzymology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/metabolism , Humans , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Inositol/chemical synthesis , Inositol/metabolism , Inositol/pharmacology , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/drug effects , Vero Cells , alpha-Glucosidases/chemistry
2.
J Med Chem ; 64(24): 18010-18024, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1555591

ABSTRACT

Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.


Subject(s)
Antiviral Agents/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Imino Sugars/pharmacology , Inositol/analogs & derivatives , alpha-Glucosidases/metabolism , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Chlorocebus aethiops , Crystallography, X-Ray , Dengue Virus/drug effects , Endoplasmic Reticulum/enzymology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/metabolism , Humans , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Inositol/chemical synthesis , Inositol/metabolism , Inositol/pharmacology , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/drug effects , Vero Cells , alpha-Glucosidases/chemistry
3.
Int J Mol Sci ; 22(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1480792

ABSTRACT

The infection of mammalian cells by enveloped viruses is triggered by the interaction of viral envelope glycoproteins with the glycosaminoglycan, heparan sulfate. By mimicking this carbohydrate, some anionic polysaccharides can block this interaction and inhibit viral entry and infection. As heparan sulfate carries both carboxyl and sulfate groups, this work focused on the derivatization of a (1→3)(1→6)-ß-D-glucan, botryosphaeran, with these negatively-charged groups in an attempt to improve its antiviral activity. Carboxyl and sulfonate groups were introduced by carboxymethylation and sulfonylation reactions, respectively. Three derivatives with the same degree of carboxymethylation (0.9) and different degrees of sulfonation (0.1; 0.2; 0.4) were obtained. All derivatives were chemically characterized and evaluated for their antiviral activity against herpes (HSV-1, strains KOS and AR) and dengue (DENV-2) viruses. Carboxymethylated botryosphaeran did not inhibit the viruses, while all sulfonated-carboxymethylated derivatives were able to inhibit HSV-1. DENV-2 was inhibited only by one of these derivatives with an intermediate degree of sulfonation (0.2), demonstrating that the dengue virus is more resistant to anionic ß-D-glucans than the Herpes simplex virus. By comparison with a previous study on the antiviral activity of sulfonated botryosphaerans, we conclude that the presence of carboxymethyl groups might have a detrimental effect on antiviral activity.


Subject(s)
Antiviral Agents/pharmacology , Dengue Virus/drug effects , Herpesviridae/drug effects , Sulfonic Acids/chemistry , beta-Glucans/chemistry , Animals , Antiviral Agents/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Dengue Virus/physiology , Glucans/chemistry , Glucans/pharmacology , Herpesviridae/physiology , Methylation , Vero Cells , Virus Internalization/drug effects , beta-Glucans/pharmacology
4.
Bioorg Med Chem ; 49: 116415, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1415233

ABSTRACT

Dengue remains a disease of significant concern, responsible for nearly half of all arthropod-borne disease cases across the globe. Due to the lack of potent and targeted therapeutics, palliative treatment and the adoption of preventive measures remain the only available options. Compounding the problem further, the failure of the only dengue vaccine, Dengvaxia®, also delivered a significant blow to any hopes for the treatment of dengue fever. However, the success of Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV) protease inhibitors in the past have continued to encourage researchers to investigate other viral protease targets. Dengue virus (DENV) NS2B-NS3 protease is an attractive target partly due to its role in polyprotein processing and also for being the most conserved domain in the viral genome. During the early days of the COVID-19 pandemic, a few cases of Dengue-COVID 19 co-infection were reported. In this review, we compared the substrate-peptide residue preferences and the residues lining the sub-pockets of the proteases of these two viruses and analyzed the significance of this similarity. Also, we attempted to abridge the developments in anti-dengue drug discovery in the last six years (2015-2020), focusing on critical discoveries that influenced the research.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Endopeptidases/metabolism , Dengue Virus/drug effects , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Coronavirus 3C Proteases/metabolism , Dengue Virus/enzymology , Humans , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology
5.
J Gen Virol ; 102(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1393559

ABSTRACT

Reactive oxygen species (ROS) are chemically active species which are involved in maintaining cellular and signalling processes at physiological concentrations. Therefore, cellular components that regulate redox balance are likely to play a crucial role in viral life-cycle either as promoters of viral replication or with antiviral functions. Zinc is an essential micronutrient associated with anti-oxidative systems and helps in maintaining a balanced cellular redox state. Here, we show that zinc chelation leads to induction of reactive oxygen species (ROS) in epithelial cells and addition of zinc restores ROS levels to basal state. Addition of ROS (H2O2) inhibited dengue virus (DENV) infection in a dose-dependent manner indicating that oxidative stress has adverse effects on DENV infection. ROS affects early stages of DENV replication as observed by quantitation of positive and negative strand viral RNA. We observed that addition of ROS specifically affected viral titres of positive strand RNA viruses. We further demonstrate that ROS specifically altered SEC31A expression at the ER suggesting a role for SEC31A-mediated pathways in the life-cycle of positive strand RNA viruses and provides an opportunity to identify drug targets regulating oxidative stress responses for antiviral development.


Subject(s)
Dengue Virus/drug effects , Hydrogen Peroxide/pharmacology , Reactive Oxygen Species/pharmacology , Virus Replication , Zinc/pharmacology , Adolescent , Aedes , Animals , Caco-2 Cells , Child , Child, Preschool , Chlorocebus aethiops , Cricetinae , Dengue/virology , Dengue Virus/physiology , Humans , Oxidative Stress , RNA, Viral
6.
Front Immunol ; 12: 707287, 2021.
Article in English | MEDLINE | ID: covidwho-1359191

ABSTRACT

Background: The outbreak of Coronavirus disease 2019 (COVID-19) has become an international public health crisis, and the number of cases with dengue co-infection has raised concerns. Unfortunately, treatment options are currently limited or even unavailable. Thus, the aim of our study was to explore the underlying mechanisms and identify potential therapeutic targets for co-infection. Methods: To further understand the mechanisms underlying co-infection, we used a series of bioinformatics analyses to build host factor interaction networks and elucidate biological process and molecular function categories, pathway activity, tissue-specific enrichment, and potential therapeutic agents. Results: We explored the pathologic mechanisms of COVID-19 and dengue co-infection, including predisposing genes, significant pathways, biological functions, and possible drugs for intervention. In total, 460 shared host factors were collected; among them, CCL4 and AhR targets were important. To further analyze biological functions, we created a protein-protein interaction (PPI) network and performed Molecular Complex Detection (MCODE) analysis. In addition, common signaling pathways were acquired, and the toll-like receptor and NOD-like receptor signaling pathways exerted a significant effect on the interaction. Upregulated genes were identified based on the activity score of dysregulated genes, such as IL-1, Hippo, and TNF-α. We also conducted tissue-specific enrichment analysis and found ICAM-1 and CCL2 to be highly expressed in the lung. Finally, candidate drugs were screened, including resveratrol, genistein, and dexamethasone. Conclusions: This study probes host factor interaction networks for COVID-19 and dengue and provides potential drugs for clinical practice. Although the findings need to be verified, they contribute to the treatment of co-infection and the management of respiratory disease.


Subject(s)
COVID-19/drug therapy , COVID-19/pathology , Computational Biology/methods , Dengue/drug therapy , Dengue/pathology , Protein Interaction Maps/physiology , Antiviral Agents/therapeutic use , Chemokine CCL2/metabolism , Coinfection , Dengue Virus/drug effects , Dexamethasone/therapeutic use , Gene Expression Regulation/genetics , Genistein/therapeutic use , Humans , Intercellular Adhesion Molecule-1/metabolism , Lung/metabolism , Resveratrol/therapeutic use , SARS-CoV-2/drug effects , Signal Transduction
7.
Sci Rep ; 11(1): 11982, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1260953

ABSTRACT

In this study we have developed a method based on Flux Balance Analysis to identify human metabolic enzymes which can be targeted for therapeutic intervention against COVID-19. A literature search was carried out in order to identify suitable inhibitors of these enzymes, which were confirmed by docking calculations. In total, 10 targets and 12 bioactive molecules have been predicted. Among the most promising molecules we identified Triacsin C, which inhibits ACSL3, and which has been shown to be very effective against different viruses, including positive-sense single-stranded RNA viruses. Similarly, we also identified the drug Celgosivir, which has been successfully tested in cells infected with different types of viruses such as Dengue, Zika, Hepatitis C and Influenza. Finally, other drugs targeting enzymes of lipid metabolism, carbohydrate metabolism or protein palmitoylation (such as Propylthiouracil, 2-Bromopalmitate, Lipofermata, Tunicamycin, Benzyl Isothiocyanate, Tipifarnib and Lonafarnib) are also proposed.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Molecular Docking Simulation , SARS-CoV-2/drug effects , Virus Replication/drug effects , Dengue Virus/drug effects , Hepacivirus/drug effects , Zika Virus/drug effects , Zika Virus Infection/drug therapy
8.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1246687

ABSTRACT

BACKGROUND: The clinical consequences of SARS-CoV-2 and DENGUE virus co-infection are not promising. However, their treatment options are currently unavailable. Current studies have shown that quercetin is both resistant to COVID-19 and DENGUE; this study aimed to evaluate the possible functional roles and underlying mechanisms of action of quercetin as a potential molecular candidate against COVID-19 and DENGUE co-infection. METHODS: We used a series of bioinformatics analyses to understand and characterize the biological functions, pharmacological targets and therapeutic mechanisms of quercetin in COVID-19 and DENGUE co-infection. RESULTS: We revealed the clinical characteristics of COVID-19 and DENGUE, including pathological mechanisms, key inflammatory pathways and possible methods of intervention, 60 overlapping targets related to the co-infection and the drug were identified, the protein-protein interaction (PPI) was constructed and TNFα, CCL-2 and CXCL8 could become potential drug targets. Furthermore, we disclosed the signaling pathways, biological functions and upstream pathway activity of quercetin in COVID-19 and DENGUE. The analysis indicated that quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway. CONCLUSIONS: This study is the first to reveal quercetin as a pharmacological drug for COVID-19 and DENGUE co-infection. COVID-19 and DENGUE co-infection remain a potential threat to the world's public health system. Therefore, we need innovative thinking to provide admissible evidence for quercetin as a potential molecule drug for the treatment of COVID-19 and DENGUE, but the findings have not been verified in actual patients, so further clinical drug trials are needed.


Subject(s)
COVID-19/drug therapy , Dengue Virus/chemistry , Dengue/drug therapy , Quercetin/chemistry , SARS-CoV-2/chemistry , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Chemokine CCL2/chemistry , Chemokine CCL2/drug effects , Chemokine CCL2/genetics , Coinfection/drug therapy , Coinfection/genetics , Coinfection/virology , Dengue/complications , Dengue/genetics , Dengue/virology , Dengue Virus/drug effects , Humans , Interleukin-17/genetics , Interleukin-8/chemistry , Interleukin-8/drug effects , Interleukin-8/genetics , NF-kappa B/drug effects , NF-kappa B/genetics , Protein Interaction Maps/drug effects , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/chemistry , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/genetics
9.
Peptides ; 142: 170570, 2021 08.
Article in English | MEDLINE | ID: covidwho-1230711

ABSTRACT

Viruses remain one of the leading causes of animal and human disease. Some animal viral infections spread sporadically to human populations, posing a serious health risk. Particularly the emerging viral zoonotic diseases such as the novel, zoonotic coronavirus represent an actual challenge for the scientific and medical community. Besides human health risks, some animal viral infections, although still not zoonotic, represent important economic loses to the livestock industry. Viral infections pose a genuine concern for which there has been an increasing interest for new antiviral molecules. Among these novel compounds, antiviral peptides have been proposed as promising therapeutic options, not only for the growing body of evidence showing hopeful results but also due to the many adverse effects of chemical-based drugs. Here we review the current progress, key targets and considerations for the development of antiviral peptides (AVPs). The review summarizes the state of the art of the AVPs tested in zoonotic (coronaviruses, Rift Valley fever viruses, Eastern Equine Encephalitis Virus, Dengue and Junín virus) and also non-zoonotic farm animal viruses (avian and cattle viruses). Their molecular target, amino acid sequence and mechanism of action are summarized and reviewed. Antiviral peptides are currently on the cutting edge since they have been reported to display anti-coronavirus activity. Particularly, the review will discuss the specific mode of action of AVPs that specifically inhibit the fusion of viral and host-cell membranes for SARS-CoV-2, showing in detail some important features of the fusion inhibiting peptides that target the spike protein of these risky viruses.


Subject(s)
Peptides/pharmacology , Viral Zoonoses/drug therapy , Viruses/drug effects , Animals , Antiviral Agents/pharmacology , Dengue Virus/drug effects , Encephalitis Virus, Eastern Equine/drug effects , Humans , Junin virus/drug effects , Rift Valley fever virus/drug effects , SARS-CoV-2/drug effects
10.
Rev Med Virol ; 31(6): e2228, 2021 11.
Article in English | MEDLINE | ID: covidwho-1126517

ABSTRACT

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.


Subject(s)
Chikungunya Fever/drug therapy , Chloroquine/therapeutic use , HIV Infections/drug therapy , Hepatitis C, Chronic/drug therapy , Hydroxychloroquine/therapeutic use , Infectious Mononucleosis/drug therapy , Severe Dengue/drug therapy , Warts/drug therapy , Alphapapillomavirus/drug effects , Alphapapillomavirus/immunology , Alphapapillomavirus/pathogenicity , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Chikungunya Fever/immunology , Chikungunya Fever/pathology , Chikungunya Fever/virology , Chikungunya virus/drug effects , Chikungunya virus/immunology , Chikungunya virus/pathogenicity , Dengue Virus/drug effects , Dengue Virus/immunology , Dengue Virus/pathogenicity , HIV/drug effects , HIV/immunology , HIV/pathogenicity , HIV Infections/immunology , HIV Infections/pathology , HIV Infections/virology , Hepacivirus/drug effects , Hepacivirus/immunology , Hepacivirus/pathogenicity , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/pathology , Hepatitis C, Chronic/virology , Herpesvirus 4, Human/drug effects , Herpesvirus 4, Human/immunology , Herpesvirus 4, Human/pathogenicity , Humans , Infectious Mononucleosis/immunology , Infectious Mononucleosis/pathology , Infectious Mononucleosis/virology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severe Dengue/immunology , Severe Dengue/pathology , Severe Dengue/virology , Treatment Outcome , Warts/immunology , Warts/pathology , Warts/virology
11.
Biomolecules ; 11(1)2020 12 24.
Article in English | MEDLINE | ID: covidwho-1067684

ABSTRACT

Phenolic compounds have been related to multiple biological activities, and the antiviral effect of these compounds has been demonstrated in several viral models of public health concern. In this review, we show the antiviral role of phenolic compounds against dengue virus (DENV), the most widespread arbovirus globally that, after its re-emergence, has caused multiple epidemic outbreaks, especially in the last two years. Twenty phenolic compounds with anti-DENV activity are discussed, including the multiple mechanisms of action, such as those directed against viral particles or viral proteins, host proteins or pathways related to the productive replication viral cycle and the spread of the infection.


Subject(s)
Antiviral Agents/therapeutic use , Dengue/drug therapy , Phenols/therapeutic use , Virus Replication/drug effects , Animals , Chlorocebus aethiops , Dengue/genetics , Dengue/pathology , Dengue/virology , Dengue Virus/drug effects , Dengue Virus/genetics , Dengue Virus/pathogenicity , Humans , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Vero Cells/drug effects , Viral Proteins/antagonists & inhibitors , Viral Proteins/genetics
12.
ACS Infect Dis ; 7(2): 471-478, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1006383

ABSTRACT

A series of 7-deazaadenine ribonucleosides bearing alkyl, alkenyl, alkynyl, aryl, or hetaryl groups at position 7 as well as their 5'-O-triphosphates and two types of monophosphate prodrugs (phosphoramidates and S-acylthioethanol esters) were prepared and tested for antiviral activity against selected RNA viruses (Dengue, Zika, tick-borne encephalitis, West Nile, and SARS-CoV-2). The modified triphosphates inhibited the viral RNA-dependent RNA polymerases at micromolar concentrations through the incorporation of the modified nucleotide and stopping a further extension of the RNA chain. 7-Deazaadenosine nucleosides bearing ethynyl or small hetaryl groups at position 7 showed (sub)micromolar antiviral activities but significant cytotoxicity, whereas the nucleosides bearing bulkier heterocycles were still active but less toxic. Unexpectedly, the monophosphate prodrugs were similarly or less active than the corresponding nucleosides in the in vitro antiviral assays, although the bis(S-acylthioethanol) prodrug 14h was transported to the Huh7 cells and efficiently released the nucleoside monophosphate.


Subject(s)
Antiviral Agents/pharmacology , Prodrugs/pharmacology , Purines/pharmacology , RNA Viruses/drug effects , Ribonucleosides/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cell Line, Tumor , Dengue Virus/drug effects , Encephalitis Viruses, Tick-Borne/drug effects , Humans , Phosphates/pharmacology , Purine Nucleosides , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/drug effects , West Nile virus/drug effects , Zika Virus/drug effects
13.
Trends Parasitol ; 37(1): 48-64, 2021 01.
Article in English | MEDLINE | ID: covidwho-943553

ABSTRACT

Here we tell the story of ivermectin, describing its anthelmintic and insecticidal actions and recent studies that have sought to reposition ivermectin for the treatment of other diseases that are not caused by helminth and insect parasites. The standard theory of its anthelmintic and insecticidal mode of action is that it is a selective positive allosteric modulator of glutamate-gated chloride channels found in nematodes and insects. At higher concentrations, ivermectin also acts as an allosteric modulator of ion channels found in host central nervous systems. In addition, in tissue culture, at concentrations higher than anthelmintic concentrations, ivermectin shows antiviral, antimalarial, antimetabolic, and anticancer effects. Caution is required before extrapolating from these preliminary repositioning experiments to clinical use, particularly for Covid-19 treatment, because of the high concentrations of ivermectin used in tissue-culture experiments.


Subject(s)
Anthelmintics/pharmacology , Insecticides/pharmacology , Ivermectin/pharmacology , Animals , Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cell Line , Chloride Channels/drug effects , Dengue Virus/drug effects , Ion Channels/drug effects , Nematoda/drug effects , SARS-CoV-2/drug effects
14.
Nat Rev Immunol ; 20(10): 633-643, 2020 10.
Article in English | MEDLINE | ID: covidwho-711937

ABSTRACT

Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Viral/administration & dosage , Antibody-Dependent Enhancement/drug effects , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Leukocytes/drug effects , Pneumonia, Viral/drug therapy , Receptors, IgG/immunology , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/biosynthesis , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/adverse effects , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dengue/drug therapy , Dengue/immunology , Dengue/virology , Dengue Virus/drug effects , Dengue Virus/immunology , Dengue Virus/pathogenicity , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Leukocytes/immunology , Leukocytes/virology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Receptors, IgG/antagonists & inhibitors , Receptors, IgG/genetics , SARS Virus/drug effects , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Signal Transduction , Virus Internalization/drug effects
15.
Microbiol Immunol ; 64(9): 635-639, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-613452

ABSTRACT

In this study, the anti-severe acute respiratory syndrome coronavirus-2 (anti-SARS-CoV-2) activity of mycophenolic acid (MPA) and IMD-0354 was analyzed. These compounds were chosen based on their antiviral activities against other coronaviruses. Because they also inhibit dengue virus (DENV) infection, other anti-DENV compounds/drugs were also assessed. On SARS-CoV-2-infected VeroE6/TMPRSS2 monolayers, both MPA and IMD-0354, but not other anti-DENV compounds/drugs, showed significant anti-SARS-CoV-2 activity. Although MPA reduced the viral RNA level by only approximately 100-fold, its half maximal effective concentration was as low as 0.87 µ m, which is easily achievable at therapeutic doses of mycophenolate mofetil. MPA targets the coronaviral papain-like protease and an in-depth study on its mechanism of action would be useful in the development of novel anti-SARS-CoV-2 drugs.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Mycophenolic Acid/pharmacology , Pneumonia, Viral/drug therapy , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/virology , Dengue Virus/drug effects , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Vero Cells , Virus Replication/drug effects
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