Predicting The Possible Biological Markers as Targeted Therapy for Dengue Viral Infections (original) (raw)
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In-silico Characterization of Target Protein in Dengue Infection
International Journal of Scientific Research in Science and Technology, 2022
Infection of humans with the virus is primarily mediated by the Aedes mosquito. The virus grows in the mosquito gut and migrates to aq 1 the salivary glands.. Dengue virus (DENV), which includes four serotypes (DENV1–4), is transmitted to humans by Aedes mosquitos and is the etiological agent of dengue fever and dengue hemorrhagic fever. DENV causes an estimated 50–100 million cases of dengue fever, 500,000 cases of severe dengue (dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)), and more than 20,000 deaths each year in tropical and subtropical regions, representing a considerable public health threat in over 100 countries worldwide. However, there are still no specific antiviral drugs or licensed vaccines against DENV infection. Dengue virus primarily propagates in skin dendritic cells, and subsequently virus proliferation is thought to occur in target cells such as those of the monocyte/macrophage lineage. Second, carbohydrate binding proteins, termed lectins, expressed on dendritic cells (DCs) and macrophages under the human skin are involved in initial contact of DENV introduced by mosquito bite. Among these lectins, dendritic cell-specific intercellular adhesion molecule-3-grabbing non integrin (DCSIGN) has been best characterized in virus-DC interaction.
In silico antigenic site evaluation and antiviral therapy against dengue serotypes
Nonstructural protein 3 (NS3) constitute protease, helicase and polymerase that are essential for dengue virus replication. The aim of the present study is to block the replication of the virus by targeting the NS3 Protein. The retrieved sequences of NS3 protein from National Centre for Biotechnology information shows that the antigenic sites of the protein are highly variable in all the four serotypes of dengue virus (DENV) i.e. DENV I, DENV II, DENV III and DENV IV. DENV III found to be most distantly related serotype among all the serotypes studied using UPGMA method. The 3D structure of NS3 protein was modeled using homology modeling by MODELLER 9v8. Evaluation of the constructed NS3 protein models were done by PROCHECK, WhatIf using Exome Horizon. The derived compounds of mycophenolic acid and ribavirin were docked as ligands to the constructed models of NS3 protein using AutoDock 4.2 for Protein-ligand interaction study.
Discovery of antiviral molecules for dengue: In silico search and biological evaluation
European Journal of Medicinal Chemistry, 2016
Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation. Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that are capable of inhibiting the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrate and the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that were capable of inhibiting this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and-13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested. Conclusions: Chemicals CID54681617, CID54692801 and CID54715399 were strong inhibitors of NS2B/NS3, with IC 50 values (µM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9 %, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors. General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.
Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway
Genetics and Molecular Research, 2015
Dengue virus (DENV) belongs to the family Flaviviridae and can cause major health problems worldwide, including dengue fever and dengue shock syndrome. DENV replicon in human cells inhibits interferon α and β with the help of its non-structural proteins. Nonstructural protein 5 (NS5) of DENV is responsible for the proteasomemediated degradation of signal transducer and activator of transcription B. Aslam et al.
Kinome siRNA screen identifies novel cell-type specific dengue host target genes
Antiviral research, 2014
Dengue is a global emerging infectious disease, with no specific treatment available. To identify novel human host cell targets important for dengue virus infection and replication, an image-based high-throughput siRNA assay screening of a human kinome siRNA library was conducted using human hepatocyte cell line Huh7 infected with a recent dengue serotype 2 virus isolate BR DEN2 01-01. In the primary siRNA screening of 779 kinase-related genes, knockdown of 22 genes showed a reduction in DENV-2 infection. Conversely, knockdown of 8 genes enhanced viral infection. To assess host cell specificity, the confirmed hits were tested in the DENV-infected monocytic cell line U937. While the expression of EIF2AK3, ETNK2 and SMAD7 was regulated in both cell lines after infection, most kinases were hepatocyte-specific. Monocytic cells represent initial targets of infection and an antiviral treatment targeting these cells is probably most effective to reduce initial viral load. In turn, infectio...
Scientific African, 2021
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Viruses
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, respectiv...
Molecular Mechanisms of Antiviral Agents against Dengue Virus
Viruses
Dengue is a major global health threat causing 390 million dengue infections and 25,000 deaths annually. The lack of efficacy of the licensed Dengvaxia vaccine and the absence of a clinically approved antiviral against dengue virus (DENV) drive the urgent demand for the development of novel anti-DENV therapeutics. Various antiviral agents have been developed and investigated for their anti-DENV activities. This review discusses the mechanisms of action employed by various antiviral agents against DENV. The development of host-directed antivirals targeting host receptors and direct-acting antivirals targeting DENV structural and non-structural proteins are reviewed. In addition, the development of antivirals that target different stages during post-infection such as viral replication, viral maturation, and viral assembly are reviewed. Antiviral agents designed based on these molecular mechanisms of action could lead to the discovery and development of novel anti-DENV therapeutics for...
3 Biotech, 2023
The non-structural protein 5 (NS5) is the most conserved protein among flaviviruses, a family that includes the dengue virus. It functions both as an RNA-dependent RNA polymerase and an RNA-methyltransferase and is therefore essential for the replication of viral RNA. The discovery that dengue virus NS5 protein (DENV-NS5) can also localize to the nucleus has resulted in renewed interest in its potential roles at the host-virus interface. In this study, we have used two complementary computational approaches in parallel – one based on linear motifs (ELM) and another based on tertiary structure of the protein (DALI) – to predict the host proteins that DENV-NS5 might interact with. Of the 42 human proteins predicted by both these methods, 34 are novel. Pathway analysis of these 42 human proteins shows that they are involved in key host cellular processes related to cell cycle regulation, proliferation, protein degradation, apoptosis, and immune responses. A focused analysis of transcription factors that directly interact with the predicted DENV-NS5 interacting proteins was performed, followed by the identification of downstream genes that are differentially expressed after dengue infection using previously published RNA-seq data. Our study provides unique insights into the DENV-NS5 interaction network and delineates mechanisms whereby DENV-NS5 could impact the host-virus interface. The novel interactors identified in this study could be potentially targeted by NS5 to modulate the host cellular environment in general, and the immune response in particular, thereby extending the role of DENV-NS5 beyond its known enzymatic functions.