Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry.

ABSTRACT: 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 GP1,2 and its different roles in filovirus entry. We first describe the latest advances on the characterization of GP gene-overlapping proteins sGP, ssGP and ?-peptide. Then, we compare filovirus surface GP1,2 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.

SUBMITTER: Martin B

PROVIDER: S-EPMC7113884 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry.

Martin Baptiste B Hoenen Thomas T Canard Bruno B Decroly Etienne E

Antiviral research 20160914

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<sub>1,2</sub> 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<sub>1,2</sub> proteins in terms of structure, synthesis and function. As they bear potential in dr ...[more]

PMID: 27640102

Similar Datasets

Flavivirus NS4B protein: Structure, function, and antiviral discovery.

Project description:Infections with mosquito-borne flaviviruses, such as Dengue virus, ZIKV virus, and West Nile virus, pose significant threats to public health. Flaviviruses cause up to 400 million infections each year, leading to many forms of diseases, including fatal hemorrhage, encephalitis, congenital abnormalities, and deaths. Currently, there are no clinically approved antiviral drugs for the treatment of flavivirus infections. The non-structural protein NS4B is an emerging target for drug discovery due to its multiple roles in the flaviviral life cycle. In this review, we summarize the latest knowledge on the structure and function of flavivirus NS4B, as well as the progress on antiviral compounds that target NS4B.

| S-EPMC10294551 | biostudies-literature

Current Landscape of Antiviral Drug Discovery.

Project description:Continued discovery and development of new antiviral medications are paramount for global human health, particularly as new pathogens emerge and old ones evolve to evade current therapeutic agents. Great success has been achieved in developing effective therapies to suppress human immunodeficiency virus (HIV) and hepatitis B virus (HBV); however, the therapies are not curative and therefore current efforts in HIV and HBV drug discovery are directed toward longer-acting therapies and/or developing new mechanisms of action that could potentially lead to cure, or eradication, of the virus. Recently, exciting early clinical data have been reported for novel antivirals targeting respiratory syncytial virus (RSV) and influenza (flu). Preclinical data suggest that these new approaches may be effective in treating high-risk patients afflicted with serious RSV or flu infections. In this review, we highlight new directions in antiviral approaches for HIV, HBV, and acute respiratory virus infections.

| S-EPMC4765712 | biostudies-other

SLC Transporters: Structure, Function, and Drug Discovery.

Project description:The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters' structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediate transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.

| S-EPMC5034948 | biostudies-literature

Characterization of the Filovirus-Resistant Cell Line SH-SY5Y Reveals Redundant Role of Cell Surface Entry Factors

Project description:Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann–Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.

2019-03-31 | GSE104008 | GEO

The Glycoproteins of All Filovirus Species Use the Same Host Factors for Entry into Bat and Human Cells but Entry Efficiency Is Species Dependent.

Project description:Ebola and marburgviruses, members of the family Filoviridae, can cause severe hemorrhagic fever in humans. The ongoing Ebola virus (EBOV) disease epidemic in Western Africa claimed more than 11,300 lives and was associated with secondary cases outside Africa, demonstrating that filoviruses pose a global health threat. Bats constitute an important natural reservoir of filoviruses, including viruses of the recently identified Cuevavirus genus within the Filoviridae family. However, the interactions of filoviruses with bat cells are incompletely understood. Here, we investigated whether filoviruses employ different strategies to enter human and bat cells. For this, we examined host cell entry driven by glycoproteins (GP) from all filovirus species into cell lines of human and fruit bat origin. We show that all GPs were able to mediate entry into human and most fruit bat cell lines with roughly comparable efficiency. In contrast, the efficiency of entry into the cell line EidNi/41 derived from a straw-colored fruit bat varied markedly between the GPs of different filovirus species. Furthermore, inhibition studies demonstrated that filoviruses employ the same host cell factors for entry into human, non-human primate and fruit bat cell lines, including cysteine proteases, two pore channels and NPC1 (Niemann-Pick C1 molecule). Finally, processing of GP by furin and the presence of the mucin-like domain in GP were dispensable for entry into both human and bat cell lines. Collectively, these results show that filoviruses rely on the same host cell factors for entry into human and fruit bat cells, although the efficiency of the usage of these factors might differ between filovirus species.

| S-EPMC4762945 | biostudies-literature

Actin-Myosin Interaction: Structure, Function and Drug Discovery.

Project description:Actin-myosin interactions play crucial roles in the generation of cellular force and movement. The molecular mechanism involves structural transitions at the interface between actin and myosin's catalytic domain, and within myosin's light chain domain, which contains binding sites for essential (ELC) and regulatory light chains (RLC). High-resolution crystal structures of isolated actin and myosin, along with cryo-electron micrographs of actin-myosin complexes, have been used to construct detailed structural models for actin-myosin interactions. However, these methods are limited by disorder, particularly within the light chain domain, and they do not capture the dynamics within this complex under physiological conditions in solution. Here we highlight the contributions of site-directed fluorescent probes and time-resolved fluorescence resonance energy transfer (TR-FRET) in understanding the structural dynamics of the actin-myosin complex in solution. A donor fluorescent probe on actin and an acceptor fluorescent probe on myosin, together with high performance TR-FRET, directly resolves structural states in the bound actin-myosin complex during its interaction with adenosine triphosphate (ATP). Results from these studies have profound implications for understanding the contractile function of actomyosin and establish the feasibility for the discovery of allosteric modulators of the actin-myosin interaction, with the ultimate goal of developing therapies for muscle disorders.

| S-EPMC6163256 | biostudies-literature

Filovirus entry into cells - new insights.

Project description:Filoviruses are hemorrhagic fever-causing agents that produce enveloped virions with a filamentous morphology. The viral surface glycoprotein, GP, orchestrates the surprisingly complex process by which filoviruses gain access to the cytoplasm of their host cells. GP mediates viral attachment to cells through multiple, redundant interactions with cell-surface factors. GP then induces virion internalization by a process that resembles cellular macropinocytosis. Within the endo/lysosomal pathway, GP undergoes a series of structural rearrangements, controlled by interactions with host factors, that prime and activate it to bring about fusion between the viral and cellular lipid bilayers. Membrane fusion delivers the viral nucleocapsid core into the cytoplasm, which is the site of filovirus replication. This review summarizes our understanding of the filovirus entry mechanism, with emphasis on recent findings.

| S-EPMC3322298 | biostudies-literature

Lactobacillus surface layer proteins: structure, function and applications.

Project description:Bacterial surface (S) layers are the outermost proteinaceous cell envelope structures found on members of nearly all taxonomic groups of bacteria and Archaea. They are composed of numerous identical subunits forming a symmetric, porous, lattice-like layer that completely covers the cell surface. The subunits are held together and attached to cell wall carbohydrates by non-covalent interactions, and they spontaneously reassemble in vitro by an entropy-driven process. Due to the low amino acid sequence similarity among S-layer proteins in general, verification of the presence of an S-layer on the bacterial cell surface usually requires electron microscopy. In lactobacilli, S-layer proteins have been detected on many but not all species. Lactobacillus S-layer proteins differ from those of other bacteria in their smaller size and high predicted pI. The positive charge in Lactobacillus S-layer proteins is concentrated in the more conserved cell wall binding domain, which can be either N- or C-terminal depending on the species. The more variable domain is responsible for the self-assembly of the monomers to a periodic structure. The biological functions of Lactobacillus S-layer proteins are poorly understood, but in some species S-layer proteins mediate bacterial adherence to host cells or extracellular matrix proteins or have protective or enzymatic functions. Lactobacillus S-layer proteins show potential for use as antigen carriers in live oral vaccine design because of their adhesive and immunomodulatory properties and the general non-pathogenicity of the species.

| S-EPMC3666127 | biostudies-literature

Virus-host interactomes--antiviral drug discovery.

Project description:One of the key questions in virology is how viruses, encoding relatively few genes, gain temporary or constant control over their hosts. To understand pathogenicity of a virus it is important to gain knowledge on the function of the individual viral proteins in the host cell, on their interactions with viral and cellular proteins and on the consequences of these interactions on cellular signaling pathways. A combination of transcriptomics, proteomics, high-throughput technologies and the bioinformatical analysis of the respective data help to elucidate specific cellular antiviral drug target candidates. In addition, viral and human interactome analyses indicate that different viruses target common, central human proteins for entering cellular signaling pathways and machineries which might constitute powerful broad-spectrum antiviral targets.

| S-EPMC7102765 | biostudies-literature

Structural biology in antiviral drug discovery.

Project description:Structural biology has emerged during the last thirty years as a powerful tool for rational drug discovery. Crystal structures of biological targets alone and in complex with ligands and inhibitors provide essential insights into the mechanisms of actions of enzymes, their conformational changes upon ligand binding, the architectures and interactions of binding pockets. Structure-based methods such as crystallographic fragment screening represent nowadays invaluable instruments for the identification of new biologically active compounds. In this context, three-dimensional protein structures have played essential roles for the understanding of the activity and for the design of novel antiviral agents against several different viruses. In this review, the evolution in the resolution of viral structures is analysed, along with the role of crystal structures in the discovery and optimisation of new antivirals.

| S-EPMC7185576 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data