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1.
Molecules ; 27(10)2022 May 18.
Article in English | MEDLINE | ID: covidwho-1875715

ABSTRACT

Data from the World Health Organisation show that the global incidence of dengue infection has risen drastically, with an estimated 400 million cases of dengue infection occurring annually. Despite this worrying trend, there is still no therapeutic treatment available. Herein, we investigated short peptide fragments with a varying total number of amino acid residues (peptide fragments) from previously reported dengue virus type 2 (DENV2) peptide-based inhibitors, DN58wt (GDSYIIIGVEPGQLKENWFKKGSSIGQMF), DN58opt (TWWCFYFCRRHHPFWFFYRHN), DS36wt (LITVNPIVTEKDSPVNIEAE), and DS36opt (RHWEQFYFRRRERKFWLFFW), aided by in silico approaches: peptide-protein molecular docking and 100 ns of molecular dynamics (MD) simulation via molecular mechanics using Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) methods. A library of 11,699 peptide fragments was generated, subjected to in silico calculation, and the candidates with the excellent binding affinity and shown to be stable in the DI-DIII binding pocket of DENV2 envelope (E) protein were determined. Selected peptides were synthesised using conventional Fmoc solid-phase peptide chemistry, purified by RP-HPLC, and characterised using LCMS. In vitro studies followed, to test for the peptides' toxicity and efficacy in inhibiting the DENV2 growth cycle. Our studies identified the electrostatic interaction (from free energy calculation) to be the driving stabilising force for the E protein-peptide interactions. Five key E protein residues were also identified that had the most interactions with the peptides: (polar) LYS36, ASN37, and ARG350, and (nonpolar) LEU351 and VAL354; these residues might play crucial roles in the effective binding interactions. One of the peptide fragments, DN58opt_8-13 (PFWFFYRH), showed the best inhibitory activity, at about 63% DENV2 plague reduction, compared with no treatment. This correlates well with the in silico studies in which the peptide possessed the lowest binding energy (-9.0 kcal/mol) and was maintained steadily within the binding pocket of DENV2 E protein during the MD simulations. This study demonstrates the use of computational studies to expand research on lead optimisation of antiviral peptides, thus explaining the inhibitory potential of the designed peptides.


Subject(s)
Dengue Virus , Dengue , Dengue/drug therapy , Humans , Molecular Docking Simulation , Peptide Fragments/pharmacology , Peptides/chemistry
2.
Viruses ; 13(8)2021 08 04.
Article in English | MEDLINE | ID: covidwho-1359300

ABSTRACT

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


Subject(s)
Antiviral Agents/therapeutic use , Dengue/drug therapy , Transcriptome , Adenosine Triphosphatases/antagonists & inhibitors , Adrenergic Antagonists/pharmacology , Adrenergic Antagonists/therapeutic use , Antiviral Agents/pharmacology , Brain/metabolism , Computer Simulation , Dengue/blood , Dengue/genetics , Dengue/metabolism , Drug Discovery , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Liver/metabolism , Metabolic Networks and Pathways/drug effects , NF-kappa B/metabolism , Serotonin Antagonists/pharmacology , Serotonin Antagonists/therapeutic use , Severe Dengue/blood , Severe Dengue/drug therapy , Severe Dengue/genetics , Severe Dengue/metabolism , Spleen/metabolism
3.
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
4.
Western Pac Surveill Response J ; 12(1): 35-39, 2021.
Article in English | MEDLINE | ID: covidwho-1259712

ABSTRACT

The rainy season in the Philippines is from June to October; this is when the number of dengue cases typically increases. In 2020 during this time, the world was facing the threat of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Coronavirus disease 2019 (COVID-19) and dengue viral infections have similar presentations and laboratory findings, including fever and thrombocytopenia, and there have been reports of coinfection with SARS-CoV-2 and arthropod-borne virus. Here, we report a case of SARS-CoV-2-dengue virus coinfection in the Philippines in a female aged 62 years, whose early symptom was fever and who was positive for SARS-CoV-2 and positive for dengue. Early recognition of such coinfection is important so that proper measures can be taken in the management of the patient.


Subject(s)
COVID-19/diagnosis , COVID-19/drug therapy , Coinfection , Dengue/diagnosis , Dengue/drug therapy , COVID-19/epidemiology , Dengue/epidemiology , Dengue Virus/isolation & purification , Dengue Virus/pathogenicity , Early Diagnosis , Female , Humans , Middle Aged , Philippines/epidemiology , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Treatment Outcome
5.
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
8.
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
9.
Biomolecules ; 11(1)2020 Dec 30.
Article in English | MEDLINE | ID: covidwho-1006314

ABSTRACT

While dengue virus (DENV) infection imposes a serious challenge to the survival of humans worldwide, severe acute respiratory syndrome-coronavirus (SARS-CoV) remains the most devastating pandemic in human history. A significant number of studies have shown that plant-derived substances could serve as potential candidates for the development of safe and efficacious remedies for combating these diseases. Different scientific databases were used to source for literature on plants used against these infections. Thirty-five studies described the traditional use of 25 species from 20 families for treating DENV infection with Carica papaya and Euphorbia hirta were the most widely used across different regions. 13 in vivo studies, 32 in vitro studies, and eight clinical studies were conducted on 30 species from 25 families against different DENV serotypes, while plants from 13 families were reported to inhibit different forms of SARS-CoV, all of which were investigated through in vitro studies. Phytoconstituents belonging to various chemical classes were identified to show a wide range of antiviral activity against these infections. Extensive studies on the potentials of medicinal plants are needed to confirm their efficacy. This paper reveals the capabilities of medicinal plants and their phytochemicals in inhibiting DENV and SARS-CoV infections.


Subject(s)
Carica/chemistry , Dengue Virus , Dengue/drug therapy , Euphorbia/chemistry , Phytochemicals , Plants, Medicinal/chemistry , SARS Virus , Severe Acute Respiratory Syndrome/drug therapy , Humans , Phytochemicals/chemistry , Phytochemicals/therapeutic use
10.
Am J Trop Med Hyg ; 103(5): 2005-2011, 2020 11.
Article in English | MEDLINE | ID: covidwho-807890

ABSTRACT

During the COVID-19 pandemic, distinguishing dengue from cases of COVID-19 in endemic areas can be difficult. In a tertiary hospital contending with COVID-19 during a dengue epidemic, a triage strategy of routine COVID-19 testing for febrile patients with viral prodromes was used. All febrile patients with viral prodromes and no epidemiologic risk for COVID-19 were first admitted to a designated ward for COVID-19 testing, where enhanced personal protective equipment was used by healthcare workers until COVID-19 was ruled out. From January to May 2020, 11,086 admissions were screened for COVID-19; 868 cases of COVID-19 were diagnosed in our institution, along with 380 cases of dengue. Only 8.5% (943/11,086) of suspected COVID-19 cases were concurrently tested for dengue serology due to a compatible overlapping clinical syndrome, and dengue was established as an alternative diagnosis in 2% (207/10,218) of suspected COVID-19 cases that tested negative. There were eight COVID-19 cases with likely false-positive dengue serology and one probable COVID-19/dengue coinfection. From April to May 2020, 251 admissions presenting as viral prodromes with no respiratory symptoms were screened; of those, 15 cases had COVID-19, and 2/15 had false-positive dengue IgM. Epidemiology investigations showed no healthcare-associated transmission. In a dengue epidemic season coinciding with a COVID-19 pandemic, dengue was established as an alternative diagnosis in a minority of COVID-19 suspects, likely due to early availability of basic diagnostics. Routine screening of patients with viral prodromes during a dual outbreak of COVID-19 and dengue enabled containment of COVID-19 cases masquerading as dengue with false-positive IgM.


Subject(s)
COVID-19/epidemiology , Dengue/epidemiology , Disease Outbreaks , SARS-CoV-2/isolation & purification , Adult , Aged , COVID-19/complications , COVID-19/diagnosis , COVID-19/therapy , COVID-19 Nucleic Acid Testing , Dengue/complications , Dengue/diagnosis , Dengue/drug therapy , Dengue Virus/immunology , Dengue Virus/isolation & purification , Diagnosis, Differential , Female , Humans , Immunoglobulin M/blood , Male , Middle Aged , Oropharynx/virology , RNA, Viral/isolation & purification , SARS-CoV-2/genetics , Singapore/epidemiology , Tertiary Care Centers , Triage/standards
11.
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
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