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Antiviral Research Oct 2016Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is... (Review)
Review
Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is available. RSV is a member of the non-segmented, negative-strand (NNS) group of RNA viruses and relies on its RNA-dependent RNA polymerase to transcribe and replicate its genome. Because of its essential nature and unique properties, the RSV polymerase has proven to be a good target for antiviral drugs, with one compound, ALS-8176, having already achieved clinical proof-of-concept efficacy in a human challenge study. In this article, we first provide an overview of the role of the RSV polymerase in viral mRNA transcription and genome replication. We then review past and current approaches to inhibiting the RSV polymerase, including use of nucleoside analogs and non-nucleoside inhibitors. Finally, we consider polymerase inhibitors that hold promise for treating infections with other NNS RNA viruses, including measles and Ebola.
Topics: Antiviral Agents; Clinical Trials as Topic; DNA-Directed RNA Polymerases; Deoxycytidine; Hemorrhagic Fever, Ebola; Humans; Measles; Mononegavirales; Nucleosides; RNA, Messenger; RNA-Dependent RNA Polymerase; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Transcription, Genetic; Virus Replication
PubMed: 27575793
DOI: 10.1016/j.antiviral.2016.08.006 -
Glycobiology Jan 2019Glycosylation is a biologically important protein modification process by which a carbohydrate chain is enzymatically added to a protein at a specific amino acid...
Glycosylation is a biologically important protein modification process by which a carbohydrate chain is enzymatically added to a protein at a specific amino acid residue. This process plays roles in many cellular functions, including intracellular trafficking, cell-cell signaling, protein folding and receptor binding. While glycosylation is a common host cell process, it is utilized by many pathogens as well. Protein glycosylation is widely employed by viruses for both host invasion and evasion of host immune responses. Thus better understanding of viral glycosylation functions has potential applications for improved antiviral therapeutic and vaccine development. Here, we summarize our current knowledge on the broad biological functions of glycans for the Mononegavirales, an order of enveloped negative-sense single-stranded RNA viruses of high medical importance that includes Ebola, rabies, measles and Nipah viruses. We discuss glycobiological findings by genera in alphabetical order within each of eight Mononegavirales families, namely, the bornaviruses, filoviruses, mymonaviruses, nyamiviruses, paramyxoviruses, pneumoviruses, rhabdoviruses and sunviruses.
Topics: Animals; Glycoproteins; Glycosylation; Humans; Mononegavirales; Polysaccharides; Viral Proteins
PubMed: 29878112
DOI: 10.1093/glycob/cwy053 -
Uirusu 2017Mononegaviruses are non-segmented negative-strand RNA viruses, and include measles, mumps, Marburg, and Ebola viruses. Measles virus and mumps virus, members of the... (Review)
Review
Mononegaviruses are non-segmented negative-strand RNA viruses, and include measles, mumps, Marburg, and Ebola viruses. Measles virus and mumps virus, members of the family Paramyxoviridae, are immunotropic and neurotropic, respectively. Marburg virus and Ebola virus, members of the family Filoviridae, cause highly lethal hemorrhagic fever. In this paper, I summarize the recent structural and functional studies on the viral glycoproteins (GPs) of these viruses, which have shed light on virus entry and the humoral response. The structural and functional analyses of the interaction between viral GPs and receptors/antibodies also illuminate directions toward therapeutics against the viruses.
Topics: Antibodies, Viral; Glycoproteins; Humans; Mononegavirales; Viral Proteins; Virus Internalization
PubMed: 29593155
DOI: 10.2222/jsv.67.69 -
Biology Letters Dec 2019Sampling reservoir hosts over time and space is critical to detect epizootics, predict spillover and design interventions. However, because sampling is logistically... (Meta-Analysis)
Meta-Analysis
Sampling reservoir hosts over time and space is critical to detect epizootics, predict spillover and design interventions. However, because sampling is logistically difficult and expensive, researchers rarely perform spatio-temporal sampling of many reservoir hosts. Bats are reservoirs of many virulent zoonotic pathogens such as filoviruses and henipaviruses, yet the highly mobile nature of these animals has limited optimal sampling of bat populations. To quantify the frequency of temporal sampling and to characterize the geographical scope of bat virus research, we here collated data on filovirus and henipavirus prevalence and seroprevalence in wild bats. We used a phylogenetically controlled meta-analysis to next assess temporal and spatial variation in bat virus detection estimates. Our analysis shows that only one in four bat virus studies report data longitudinally, that sampling efforts cluster geographically (e.g. filovirus data are available across much of Africa and Asia but are absent from Latin America and Oceania), and that sampling designs and reporting practices may affect some viral detection estimates (e.g. filovirus seroprevalence). Within the limited number of longitudinal bat virus studies, we observed high heterogeneity in viral detection estimates that in turn reflected both spatial and temporal variation. This suggests that spatio-temporal sampling designs are important to understand how zoonotic viruses are maintained and spread within and across wild bat populations, which in turn could help predict and preempt risks of zoonotic viral spillover.
Topics: Africa; Animals; Asia; Chiroptera; Filoviridae; Henipavirus; Seroepidemiologic Studies
PubMed: 31822244
DOI: 10.1098/rsbl.2019.0423 -
Viruses Dec 2012The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more... (Review)
Review
The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines.
Topics: Animals; Chlorocebus aethiops; Ebolavirus; Marburgvirus; Vero Cells; Viral Load; Viral Plaque Assay
PubMed: 23223188
DOI: 10.3390/v4123511 -
Antiviral Research Nov 2016This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the... (Review)
Review
This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the surface glycoprotein GP and its different roles in filovirus entry. We first describe the latest advances on the characterization of GP gene-overlapping proteins sGP, ssGP and Δ-peptide. Then, we compare filovirus surface GP proteins in terms of structure, synthesis and function. As they bear potential in drug-design, the discovery of small organic compounds inhibiting filovirus entry is a currently very active field. Although it is at an early stage, the development of antiviral drugs against Ebola and Marburg virus entry might prove essential to reduce outbreak-associated fatality rates through post-exposure treatment of both suspected and confirmed cases.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Antiviral Agents; Drug Discovery; Ebolavirus; Filoviridae; Filoviridae Infections; Glycoproteins; Humans; Marburgvirus; Mice; Viral Envelope Proteins; Virus Internalization
PubMed: 27640102
DOI: 10.1016/j.antiviral.2016.09.001 -
Journal of Microbiology, Immunology,... Apr 2015Minigenomes (MGs) are complementary DNAs of the synthetic analogs of genomic RNA. MGs are widely used to study the life cycle of the Paramyxoviridae family of viruses.... (Review)
Review
Minigenomes (MGs) are complementary DNAs of the synthetic analogs of genomic RNA. MGs are widely used to study the life cycle of the Paramyxoviridae family of viruses. MG-based studies have provided valuable insights into the mechanisms of viral replication and transcription in this family, including the roles of viral proteins, the location and boundaries of the cis-acting elements, the functional domains of trans-acting proteins, techniques for the measurement of neutralizing antibody, virus-host interactions, and the structure and function of viral RNA. This article provides a brief overview of the principle and application of MG technology in studies involving members of the Paramyxoviridae family. The advantages, potential limitations, and future scope of MG technology are also discussed.
Topics: Genome, Viral; Host-Pathogen Interactions; Molecular Biology; Paramyxoviridae; Virology; Virus Physiological Phenomena
PubMed: 24767419
DOI: 10.1016/j.jmii.2014.02.008 -
Nature Reviews. Microbiology May 2019The recent large outbreak of Ebola virus disease (EVD) in Western Africa resulted in greatly increased accumulation of human genotypic, phenotypic and clinical data, and...
The recent large outbreak of Ebola virus disease (EVD) in Western Africa resulted in greatly increased accumulation of human genotypic, phenotypic and clinical data, and improved our understanding of the spectrum of clinical manifestations. As a result, the WHO disease classification of EVD underwent major revision.
Topics: Filoviridae; Filoviridae Infections; Hemorrhagic Fever, Ebola; Humans; World Health Organization
PubMed: 30926957
DOI: 10.1038/s41579-019-0187-4 -
Viruses Aug 2023The Ebola virus and its close relative, the Marburg virus, both belong to the family Filoviridae and are highly hazardous and contagious viruses. With a mortality rate...
The Ebola virus and its close relative, the Marburg virus, both belong to the family Filoviridae and are highly hazardous and contagious viruses. With a mortality rate ranging from 23% to 90%, depending on the specific outbreak, the development of effective antiviral interventions is crucial for reducing fatalities and mitigating the impact of Marburg virus outbreaks. In this investigation, a virtual screening approach was employed to evaluate 2042 natural compounds for their potential interactions with the VP35 protein of the Marburg virus. Average and worst binding energies were calculated for all 20 poses, and compounds that exhibited binding energies <-6 kcal/mol in both criteria were selected for further analysis. Based on binding energies, only six compounds (Estradiol benzoate, INVEGA (paliperidone), Isosilybin, Protopanaxadiol, Permethrin, and Bufalin) were selected for subsequent investigations, focusing on interaction analysis. Among these selected compounds, Estradiol benzoate, INVEGA (paliperidone), and Isosilybin showed strong hydrogen bonds, while the others did not. In this study, the compounds Myricetin, Isosilybin, and Estradiol benzoate were subjected to a molecular dynamics (MD) simulation and free binding energy calculation using MM/GBSA analysis. The reference component Myricetin served as a control. Estradiol benzoate exhibited the most stable and consistent root-mean-square deviation (RMSD) values, whereas Isosilybin showed significant fluctuations in RMSD. The compound Estradiol benzoate exhibited the lowest ΔG binding free energy (-22.89 kcal/mol), surpassing the control compound's binding energy (-9.29 kcal/mol). Overall, this investigation suggested that Estradiol benzoate possesses favorable binding free energies, indicating a potential inhibitory mechanism against the VP35 protein of the Marburg virus. The study proposes that these natural compounds could serve as a therapeutic option for preventing Marburg virus infection. However, experimental validation is required to further corroborate these findings.
Topics: Marburgvirus; Cheminformatics; Paliperidone Palmitate; Gene Library; Ebolavirus
PubMed: 37632081
DOI: 10.3390/v15081739 -
MBio Jul 2019The filoviruses are etiological agents of life-threatening hemorrhagic fever with high mortality rate and risk of potential outbreak. Among members of this family, the...
The filoviruses are etiological agents of life-threatening hemorrhagic fever with high mortality rate and risk of potential outbreak. Among members of this family, the Ebola (EBOV), Sudan (SUDV), and Marburg (MARV) viruses are considered the most pathogenic for humans. The ebolavirus nucleoprotein (NP) is the most abundant protein in infected cells and is essential for viral transcription and replication; thus, it represents an attractive target for therapeutic intervention. Here, we present the structure of SUDV NP in complex with the amino-terminal portion of the phosphoprotein VP35 at 2.3 Å. This structure captures VP35 chaperoning SUDV NP in a monomeric and RNA-free state. This transient state has been proposed to be key to maintaining a pool of monomeric and RNA-free NPs prior to NP-NP polymerization and encapsidation of the viral RNA genome. This structure also reveals a newly visualized interaction between NP and VP35, a well-defined beta sheet that is not present in previous structures. Affinity binding assays demonstrate that this beta sheet is essential for maintaining the high-affinity interaction between VP35 and a hydrophobic pocket on SUDV NP, and electron microscopy indicates the importance of this binding interaction to the oligomeric state and assembly of NP in human cells. Complementary structure-directed mutagenesis identifies critical residues conserved across the filovirus family that could be targeted by broadly effective antivirals. Outbreaks of the filoviruses can be unpredictable in timing, location, and identity of the causative virus, with each of Ebola virus, Sudan virus, Bundibugyo virus, and Marburg virus reemerging in the last several years to cause human disease with 30 to 90% lethality. The 2014-2016 outbreak in particular, with nearly 30,000 patients, highlighted the ability of these viruses to emerge unexpectedly and spread rapidly. Two ebolavirus outbreaks have emerged this year, yet we still lack FDA-approved drugs with pan-filovirus activity to treat existing and emergent ebolaviruses. For all filoviruses, the interaction between the nucleoprotein and the phosphoprotein is essential for the virus life cycle and is a potential target for therapeutic intervention. In this report, we describe the crystal structure of the SUDV nucleoprotein with the interacting domain of the viral phosphoprotein, and we identify residues critical for high-affinity interaction and for control of the oligomeric state of the nucleoprotein. Structural comparison of this heterodimer with other members of the filovirus family allowed us to find conserved and essential atomic features that will facilitate understanding of the virus life cycle and the rational design of antivirals.
Topics: Crystallography, X-Ray; Ebolavirus; Filoviridae; Nucleoproteins; Phosphoproteins; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Viral Regulatory and Accessory Proteins
PubMed: 31337716
DOI: 10.1128/mBio.00734-19