Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Compound FC-10696 Inhibits Egress of Marburg Virus.

ABSTRACT: Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW domain-containing proteins via its conserved PPxY late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small-molecule compounds targeting the viral PPxY/host WW domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure-activity relationship (SAR) of a previously described series of PPxY inhibitors. We show that FC-10696 inhibits egress of mVP40 virus-like particles (VLPs) and egress of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated-mice displayed delayed onset of weight loss and clinical signs and significantly lower viral loads compared to controls, with 14% of animals surviving 21 days following a lethal MARV challenge. Thus, FC-10696 represents a first-in-class, host-oriented inhibitor effectively targeting late stages of the MARV life cycle.

SUBMITTER: Han Z

PROVIDER: S-EPMC8218653 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Host and Viral Proteins Modulating Ebola and Marburg Virus Egress.

Project description:The filoviruses Ebolavirus and Marburgvirus are among the deadliest viral pathogens known to infect humans, causing emerging diseases with fatality rates of up to 90% during some outbreaks. The replication cycles of these viruses are comprised of numerous complex molecular processes and interactions with their human host, with one key feature being the means by which nascent virions exit host cells to spread to new cells and ultimately to a new host. This review focuses on our current knowledge of filovirus egress and the viral and host factors and processes that are involved. Within the virus, these factors consist of the major matrix protein, viral protein 40 (VP40), which is necessary and sufficient for viral particle release, and nucleocapsid and glycoprotein that interact with VP40 to promote egress. In the host cell, some proteins are hijacked by filoviruses in order to enhance virion budding capacity that include members of the family of E3 ubiquitin ligase and the endosomal sorting complexes required for transport (ESCRT) pathway, while others such as tetherin inhibit viral egress. An understanding of these molecular interactions that modulate viral particle egress provides an important opportunity to identify new targets for the development of antivirals to prevent and treat filovirus infections.

| S-EPMC6357148 | biostudies-literature

Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.

Project description:We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.

| S-EPMC4955528 | biostudies-literature

Correction: Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress.

Project description:[This corrects the article DOI: 10.1371/journal.ppat.1006132.].

| S-EPMC5517035 | biostudies-literature

Transcriptomics of Marburg virus-infected proximal tubular cells

Project description:Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90%. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 hours post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response.

2024-02-14 | GSE226148 | GEO

Marburg Virus Viral Protein 35 Inhibits Protein Kinase R Activation in a Cell Type-Specific Manner.

Project description:Protein kinase R (PKR) is a key antiviral protein involved in sensing and restricting viral infections. Here we analyzed the ability of Marburg virus (MARV) viral protein 35 (VP35) to inhibit PKR activation in human and bat cells. Similar to the related Ebola and Lloviu viruses, MARV VP35 was able to inhibit PKR activation in 293T cells. In contrast, we found that MARV VP35 did not inhibit human or bat PKR activation in human glioblastoma U-251-MG cells or a Rousettus aegyptiacus cell line. Additional experiments revealed that PACT, a known PKR regulator, was insufficient to rescue the ability of VP35 to inhibit PKR activation in these cells. Taken together, this study indicates that the ability of VP35 to inhibit PKR is cell type specific, potentially explaining discrepancies between the ability of filoviruses to potently block innate immune responses, and the high levels of interferon and interferon-stimulated genes observed in filovirus patients.

| S-EPMC6249588 | biostudies-literature

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever.

Project description:Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF.

| S-EPMC5157018 | biostudies-literature

Modified vaccinia Ankara vaccine expressing Marburg virus-like particles protects guinea pigs from lethal Marburg virus infection.

Project description:We introduce a new vaccine platform against Marburg virus (MARV) combining the advantages of the immunogenicity of a highly attenuated vaccine vector (Modified Vaccinia Ankara, MVA) with the authentic conformation of virus-like particles (VLPs). Our vaccine, MVA-MARV-VLP, expresses the minimal components of MARV VLPs: the envelope glycoprotein GP and the matrix protein VP40. Electron microscopy confirmed self-assembly and budding of VLPs from infected cells. Prime/boost vaccination of guinea pigs with MVA-MARV-VLP-elicited MARV-specific binding and neutralizing antibody responses. Vaccination also induced Fc-mediated innate immune effector functions including activation of NK cells and antibody-dependent phagocytosis by neutrophils and monocytes. Inoculation of vaccinated animals with guinea pig-adapted MARV demonstrated 100% protection against death and disease with no viremia. Therefore, our vaccine platform, expressing two antigens resulting in assembly of VLPs in the native conformation in vaccinated hosts, can be used as a potent vaccine against MARV.

| S-EPMC7468113 | biostudies-literature

Crystal structure of Marburg virus VP24.

Project description:The VP24 protein plays an essential, albeit poorly understood role in the filovirus life cycle. VP24 is only 30% identical between Marburg virus and the ebolaviruses. Furthermore, VP24 from the ebolaviruses is immunosuppressive, while that of Marburg virus is not. The crystal structure of Marburg virus VP24, presented here, reveals that although the core is similar between the viral genera, Marburg VP24 is distinguished by a projecting ?-shelf and an alternate conformation of the N-terminal polypeptide.

| S-EPMC4019143 | biostudies-literature

Marburg virus in fruit bat, Kenya.

Project description: Not available

| S-EPMC2958024 | biostudies-literature

A Cloned Recombinant Vesicular Stomatitis Virus-Vectored Marburg Vaccine, PHV01, Protects Guinea Pigs from Lethal Marburg Virus Disease

Project description:Marburg virus (MARV) is a negative-sense, single-stranded RNA virus that belongs to the Filoviridae family. Despite having caused numerous outbreaks of severe hemorrhagic fever with high case fatality rates, there are still no clinically approved therapeutics or vaccines to treat or prevent MARV disease. Recombinant vesicular stomatitis viruses (rVSVs) expressing heterologous viral glycoproteins have shown remarkable promise as live-attenuated vaccine vectors, with an rVSV-based Ebola virus vaccine having received regulatory approval in the United States and numerous other countries. Analogous rVSV vaccine vectors have also been developed for MARV and have shown efficacy in several preclinical studies conducted in nonhuman primates. Here, we used a guinea pig model to confirm the protective efficacy of a cloned, rVSV-based candidate vaccine, termed PHV01, expressing the MARV variant Angola glycoprotein. Our results demonstrated that a single dose (2 × 106 PFU) of vaccine administered 28 days prior to challenge with a uniformly lethal dose of guinea-pig-adapted MARV variant Angola provided complete protection from death and disease. Moreover, protection was robust, with as little as 200 PFU of vaccine conferring significant protection. Not only does this study highlight the potential predictive value of the guinea pig model in the evaluation of MARV countermeasures, but it also demonstrates consistent and reproducible protection afforded by a clonal vaccine candidate. Indeed, this study identifies PHV01 as a suitable vaccine candidate for advanced development.

| S-EPMC9324024 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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