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1.
Viruses ; 13(12)2021 11 27.
Article in English | MEDLINE | ID: covidwho-1574265

ABSTRACT

Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.


Subject(s)
Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Virus Diseases/metabolism , Viruses/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Immunity, Innate , Inflammation , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/antagonists & inhibitors , Virus Diseases/drug therapy , Virus Diseases/immunology , Viruses/classification , Viruses/drug effects
2.
Curr Top Med Chem ; 20(11): 915-962, 2020.
Article in English | MEDLINE | ID: covidwho-1453165

ABSTRACT

BACKGROUND: Emerging viral zoonotic diseases are one of the major obstacles to secure the "One Health" concept under the current scenario. Current prophylactic, diagnostic and therapeutic approaches often associated with certain limitations and thus proved to be insufficient for customizing rapid and efficient combating strategy against the highly transmissible pathogenic infectious agents leading to the disastrous socio-economic outcome. Moreover, most of the viral zoonoses originate from the wildlife and poor knowledge about the global virome database renders it difficult to predict future outbreaks. Thus, alternative management strategy in terms of improved prophylactic vaccines and their delivery systems; rapid and efficient diagnostics and effective targeted therapeutics are the need of the hour. METHODS: Structured literature search has been performed with specific keywords in bibliographic databases for the accumulation of information regarding current nanomedicine interventions along with standard books for basic virology inputs. RESULTS: Multi-arrayed applications of nanomedicine have proved to be an effective alternative in all the aspects regarding the prevention, diagnosis, and control of zoonotic viral diseases. The current review is focused to outline the applications of nanomaterials as anti-viral vaccines or vaccine/drug delivery systems, diagnostics and directly acting therapeutic agents in combating the important zoonotic viral diseases in the recent scenario along with their potential benefits, challenges and prospects to design successful control strategies. CONCLUSION: This review provides significant introspection towards the multi-arrayed applications of nanomedicine to combat several important zoonotic viral diseases.


Subject(s)
Drug Delivery Systems/methods , Viral Vaccines/chemistry , Viral Zoonoses/diagnosis , Viral Zoonoses/prevention & control , Viral Zoonoses/therapy , Viruses/drug effects , Animals , Animals, Wild , Biosensing Techniques , Drug Carriers/chemistry , Drug Compounding , Drug Liberation , Humans , Nanomedicine , Nanoparticles/chemistry , Polymers/chemistry , Polymers/metabolism , Transfection , Viruses/metabolism
3.
Int J Mol Sci ; 21(24)2020 Dec 17.
Article in English | MEDLINE | ID: covidwho-1383876

ABSTRACT

Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cells. Interestingly, certain viruses, and, more especially, enveloped viruses belonging to different viral families and including human pathogens, can mediate cell-cell fusion between infected cells and neighboring non-infected cells. Depending of the cellular environment and tissue organization, this virus-mediated cell-cell fusion leads to the merge of membrane and cytoplasm contents and formation of multinucleated cells, also called syncytia, that can express high amount of viral antigens in tissues and organs of infected hosts. This ability of some viruses to trigger cell-cell fusion between infected cells as virus-donor cells and surrounding non-infected target cells is mainly related to virus-encoded fusion proteins, known as viral fusogens displaying high fusogenic properties, and expressed at the cell surface of the virus-donor cells. Virus-induced cell-cell fusion is then mediated by interactions of these viral fusion proteins with surface molecules or receptors involved in virus entry and expressed on neighboring non-infected cells. Thus, the goal of this review is to give an overview of the different animal virus families, with a more special focus on human pathogens, that can trigger cell-cell fusion.


Subject(s)
Cell Fusion , Cell Membrane/metabolism , Membrane Fusion , Viral Fusion Proteins/metabolism , Virus Internalization , Viruses/metabolism , Animals , Humans , Viruses/isolation & purification
4.
Front Immunol ; 12: 638573, 2021.
Article in English | MEDLINE | ID: covidwho-1376694

ABSTRACT

Animal viruses are parasites of animal cells that have characteristics such as heredity and replication. Viruses can be divided into non-enveloped and enveloped viruses if a lipid bilayer membrane surrounds them or not. All the membrane proteins of enveloped viruses that function in attachment to target cells or membrane fusion are modified by glycosylation. Glycosylation is one of the most common post-translational modifications of proteins and plays an important role in many biological behaviors, such as protein folding and stabilization, virus attachment to target cell receptors and inhibition of antibody neutralization. Glycans of the host receptors can also regulate the attachment of the viruses and then influence the virus entry. With the development of glycosylation research technology, the research and development of novel virus vaccines and antiviral drugs based on glycan have received increasing attention. Here, we review the effects of host glycans and viral proteins on biological behaviors of viruses, and the opportunities for prevention and treatment of viral infectious diseases.


Subject(s)
Host-Parasite Interactions/physiology , Polysaccharides/metabolism , Receptors, Virus/metabolism , Virus Internalization , Viruses , Animals , Glycosylation , Humans , Immune Evasion , Viruses/immunology , Viruses/metabolism
5.
Toxins (Basel) ; 13(2)2021 01 22.
Article in English | MEDLINE | ID: covidwho-1344393

ABSTRACT

Ribosome-inactivating proteins (RIPs) are rRNA N-glycosylases from plants (EC 3.2.2.22) that inactivate ribosomes thus inhibiting protein synthesis. The antiviral properties of RIPs have been investigated for more than four decades. However, interest in these proteins is rising due to the emergence of infectious diseases caused by new viruses and the difficulty in treating viral infections. On the other hand, there is a growing need to control crop diseases without resorting to the use of phytosanitary products which are very harmful to the environment and in this respect, RIPs have been shown as a promising tool that can be used to obtain transgenic plants resistant to viruses. The way in which RIPs exert their antiviral effect continues to be the subject of intense research and several mechanisms of action have been proposed. The purpose of this review is to examine the research studies that deal with this matter, placing special emphasis on the most recent findings.


Subject(s)
Antiviral Agents/pharmacology , Pest Control, Biological , Plant Diseases/prevention & control , Plants, Genetically Modified/enzymology , Protein Synthesis Inhibitors/pharmacology , Ribosome Inactivating Proteins/pharmacology , Toxins, Biological/pharmacology , Virus Diseases/drug therapy , Viruses/drug effects , Animals , Antiviral Agents/isolation & purification , Humans , Plant Diseases/genetics , Plant Diseases/virology , Plants, Genetically Modified/genetics , Plants, Genetically Modified/virology , Protein Synthesis Inhibitors/isolation & purification , Ribosome Inactivating Proteins/isolation & purification , Toxins, Biological/isolation & purification , Virus Diseases/metabolism , Virus Diseases/virology , Viruses/metabolism , Viruses/pathogenicity
6.
Molecules ; 26(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1304689

ABSTRACT

Antiviral action of various photosensitizers is already summarized in several comprehensive reviews, and various mechanisms have been proposed for it. However, a critical consideration of the matter of the area is complicated, since the exact mechanisms are very difficult to explore and clarify, and most publications are of an empirical and "phenomenological" nature, reporting a dependence of the antiviral action on illumination, or a correlation of activity with the photophysical properties of the substances. Of particular interest is substance-assisted photogeneration of highly reactive singlet oxygen (1O2). The damaging action of 1O2 on the lipids of the viral envelope can probably lead to a loss of the ability of the lipid bilayer of enveloped viruses to fuse with the lipid membrane of the host cell. Thus, lipid bilayer-affine 1O2 photosensitizers have prospects as broad-spectrum antivirals against enveloped viruses. In this short review, we want to point out the main types of antiviral photosensitizers with potential affinity to the lipid bilayer and summarize the data on new compounds over the past three years. Further understanding of the data in the field will spur a targeted search for substances with antiviral activity against enveloped viruses among photosensitizers able to bind to the lipid membranes.


Subject(s)
Antiviral Agents , Membrane Lipids/metabolism , Photosensitizing Agents , Viral Envelope/metabolism , Virus Diseases , Viruses/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Humans , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacokinetics , Photosensitizing Agents/therapeutic use , Singlet Oxygen , Virus Diseases/drug therapy , Virus Diseases/metabolism
7.
Biomolecules ; 11(6)2021 06 02.
Article in English | MEDLINE | ID: covidwho-1257986

ABSTRACT

Carbohydrates have long been known to mediate intracellular interactions, whether within one organism or between different organisms. Sialic acids (Sias) are carbohydrates that usually occupy the terminal positions in longer carbohydrate chains, which makes them common recognition targets mediating these interactions. In this review, we summarize the knowledge about animal disease-causing agents such as viruses, bacteria and protozoa (including the malaria parasite Plasmodium falciparum) in which Sias play a role in infection biology. While Sias may promote binding of, e.g., influenza viruses and SV40, they act as decoys for betacoronaviruses. The presence of two common forms of Sias, Neu5Ac and Neu5Gc, is species-specific, and in humans, the enzyme converting Neu5Ac to Neu5Gc (CMAH, CMP-Neu5Ac hydroxylase) is lost, most likely due to adaptation to pathogen regimes; we discuss the research about the influence of malaria on this trait. In addition, we present data suggesting the CMAH gene was probably present in the ancestor of animals, shedding light on its glycobiology. We predict that a better understanding of the role of Sias in disease vectors would lead to more effective clinical interventions.


Subject(s)
Bacteria/metabolism , Mixed Function Oxygenases/metabolism , N-Acetylneuraminic Acid/metabolism , Plasmodium falciparum/metabolism , Viruses/metabolism , Animals , Humans
8.
Viruses ; 13(7)2021 06 25.
Article in English | MEDLINE | ID: covidwho-1289022

ABSTRACT

Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by "priming" and/or "activation" steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.


Subject(s)
Gene Expression Regulation, Viral , Proprotein Convertases/metabolism , Virus Diseases/virology , Virus Internalization , Viruses/genetics , Biological Transport , Furin/metabolism , Humans , Proprotein Convertase 9/metabolism , Proprotein Convertases/genetics , Proteolysis , SARS-CoV-2/enzymology , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope/metabolism , Viruses/metabolism
9.
Viruses ; 13(7)2021 06 30.
Article in English | MEDLINE | ID: covidwho-1287278

ABSTRACT

Host plasma membrane protein SERINC5 is incorporated into budding retrovirus particles where it blocks subsequent entry into susceptible target cells. Three structurally unrelated proteins encoded by diverse retroviruses, human immunodeficiency virus type 1 (HIV-1) Nef, equine infectious anemia virus (EIAV) S2, and ecotropic murine leukemia virus (MLV) GlycoGag, disrupt SERINC5 antiviral activity by redirecting SERINC5 from the site of virion assembly on the plasma membrane to an internal RAB7+ endosomal compartment. Pseudotyping retroviruses with particular glycoproteins, e.g., vesicular stomatitis virus glycoprotein (VSV G), renders the infectivity of particles resistant to inhibition by virion-associated SERINC5. To better understand viral determinants for SERINC5-sensitivity, the effect of SERINC5 was assessed using HIV-1, MLV, and Mason-Pfizer monkey virus (M-PMV) virion cores, pseudotyped with glycoproteins from Arenavirus, Coronavirus, Filovirus, Rhabdovirus, Paramyxovirus, and Orthomyxovirus genera. SERINC5 restricted virions pseudotyped with glycoproteins from several retroviruses, an orthomyxovirus, a rhabdovirus, a paramyxovirus, and an arenavirus. Infectivity of particles pseudotyped with HIV-1, amphotropic-MLV (A-MLV), or influenza A virus (IAV) glycoproteins, was decreased by SERINC5, whether the core was provided by HIV-1, MLV, or M-PMV. In contrast, particles pseudotyped with glycoproteins from M-PMV, parainfluenza virus 5 (PIV5), or rabies virus (RABV) were sensitive to SERINC5, but only with particular retroviral cores. Resistance to SERINC5 did not correlate with reduced SERINC5 incorporation into particles, route of viral entry, or absolute infectivity of the pseudotyped virions. These findings indicate that some non-retroviruses may be sensitive to SERINC5 and that, in addition to the viral glycoprotein, the retroviral core influences sensitivity to SERINC5.


Subject(s)
Host-Pathogen Interactions , Membrane Proteins/genetics , Viral Envelope Proteins , Virion/metabolism , Viruses/metabolism , HEK293 Cells , HIV-1/metabolism , Humans , Leukemia Virus, Murine/metabolism , Membrane Proteins/immunology , Retroviridae/classification , Retroviridae/metabolism , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Virion/genetics , Virus Internalization , Viruses/chemistry , Viruses/classification , Viruses/genetics
10.
Brief Bioinform ; 22(5)2021 09 02.
Article in English | MEDLINE | ID: covidwho-1122600

ABSTRACT

The protein-protein interactions (PPIs) between human and viruses mediate viral infection and host immunity processes. Therefore, the study of human-virus PPIs can help us understand the principles of human-virus relationships and can thus guide the development of highly effective drugs to break the transmission of viral infectious diseases. Recent years have witnessed the rapid accumulation of experimentally identified human-virus PPI data, which provides an unprecedented opportunity for bioinformatics studies revolving around human-virus PPIs. In this article, we provide a comprehensive overview of computational studies on human-virus PPIs, especially focusing on the method development for human-virus PPI predictions. We briefly introduce the experimental detection methods and existing database resources of human-virus PPIs, and then discuss the research progress in the development of computational prediction methods. In particular, we elaborate the machine learning-based prediction methods and highlight the need to embrace state-of-the-art deep-learning algorithms and new feature engineering techniques (e.g. the protein embedding technique derived from natural language processing). To further advance the understanding in this research topic, we also outline the practical applications of the human-virus interactome in fundamental biological discovery and new antiviral therapy development.


Subject(s)
Host-Pathogen Interactions/genetics , Machine Learning , Protein Interaction Mapping/methods , Receptors, Virus/metabolism , Viral Proteins/metabolism , Viruses/metabolism , Amino Acid Sequence , Antiviral Agents/therapeutic use , CD40 Antigens/genetics , CD40 Antigens/metabolism , Computational Biology/methods , Databases, Genetic , Gene Expression , Humans , Protein Binding , Receptors, Virus/genetics , TNF Receptor-Associated Factor 3/genetics , TNF Receptor-Associated Factor 3/metabolism , Viral Proteins/genetics , Virus Diseases/drug therapy , Virus Diseases/virology , Viruses/drug effects , Viruses/genetics
11.
Methods Mol Biol ; 2256: 217-236, 2021.
Article in English | MEDLINE | ID: covidwho-1235682

ABSTRACT

Viruses have evolved to interact with their hosts. Some viruses such as human papilloma virus, dengue virus, SARS-CoV, or influenza virus encode proteins including a PBM that interact with cellular proteins containing PDZ domains. There are more than 400 cellular protein isoforms with these domains in the human genome, indicating that viral PBMs have a high potential to influence the behavior of the cell. In this review we analyze the most relevant cellular processes known to be affected by viral PBM-cellular PDZ interactions including the establishment of cell-cell interactions and cell polarity, the regulation of cell survival and apoptosis and the activation of the immune system. Special attention has been provided to coronavirus PBM conservation throughout evolution and to the role of the PBMs of human coronaviruses SARS-CoV and MERS-CoV in pathogenesis.


Subject(s)
Cell Adhesion Molecules/metabolism , Host-Pathogen Interactions , Viral Proteins/metabolism , Virus Diseases/metabolism , Viruses/metabolism , Apoptosis/physiology , Cell Proliferation/physiology , Humans , PDZ Domains , Protein Binding , Protein Structure, Secondary , Virus Diseases/virology , Viruses/isolation & purification
12.
Viruses ; 12(10)2020 10 03.
Article in English | MEDLINE | ID: covidwho-1224248

ABSTRACT

Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such as cell signaling, the establishment of organelle identity, and the regulation of cytoskeleton and membrane dynamics. As expected, given their pleiotropic regulatory functions, they have key functions in viral replication. The spatial restriction and steady-state levels of each phosphoinositide depend primarily on the concerted action of specific phosphoinositide kinases and phosphatases. This review focuses on a number of remarkable examples of viral strategies involving phosphoinositide kinases to ensure effective viral replication.


Subject(s)
Phosphatidylinositol Phosphates/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Virus Diseases/metabolism , Virus Replication/physiology , Animals , Caenorhabditis elegans Proteins , Humans , Organelles/metabolism , Phosphatidylinositols/metabolism , Phosphoric Monoester Hydrolases/metabolism , Phosphotransferases/metabolism , Signal Transduction , Viruses/metabolism
13.
Viruses ; 12(11)2020 10 25.
Article in English | MEDLINE | ID: covidwho-896046

ABSTRACT

The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.


Subject(s)
Oxygen/metabolism , Signal Transduction , Viral Tropism , Virus Replication , Viruses/pathogenicity , Animals , Humans , Hypoxia , Hypoxia-Inducible Factor 1/metabolism , Mice , Repressor Proteins/metabolism , Viruses/classification , Viruses/metabolism
14.
Brief Bioinform ; 22(4)2021 07 20.
Article in English | MEDLINE | ID: covidwho-893102

ABSTRACT

In viruses, posttranslational modifications (PTMs) are essential for their life cycle. Recognizing viral PTMs is very important for a better understanding of the mechanism of viral infections and finding potential drug targets. However, few studies have investigated the roles of viral PTMs in virus-human interactions using comprehensive viral PTM datasets. To fill this gap, we developed the first comprehensive viral posttranslational modification database (VPTMdb) for collecting systematic information of PTMs in human viruses and infected host cells. The VPTMdb contains 1240 unique viral PTM sites with 8 modification types from 43 viruses (818 experimentally verified PTM sites manually extracted from 150 publications and 422 PTMs extracted from SwissProt) as well as 13 650 infected cells' PTMs extracted from seven global proteomics experiments in six human viruses. The investigation of viral PTM sequences motifs showed that most viral PTMs have the consensus motifs with human proteins in phosphorylation and five cellular kinase families phosphorylate more than 10 viral species. The analysis of protein disordered regions presented that more than 50% glycosylation sites of double-strand DNA viruses are in the disordered regions, whereas single-strand RNA and retroviruses prefer ordered regions. Domain-domain interaction analysis indicating potential roles of viral PTMs play in infections. The findings should make an important contribution to the field of virus-human interaction. Moreover, we created a novel sequence-based classifier named VPTMpre to help users predict viral protein phosphorylation sites. VPTMdb online web server (http://vptmdb.com:8787/VPTMdb/) was implemented for users to download viral PTM data and predict phosphorylation sites of interest.


Subject(s)
Databases, Genetic , Host-Pathogen Interactions , Protein Processing, Post-Translational , Viral Proteins , Virus Physiological Phenomena , Viruses , Amino Acid Motifs , Humans , Internet , Phosphorylation/genetics , Protein Kinases/genetics , Protein Kinases/metabolism , Proteomics , Viral Proteins/genetics , Viral Proteins/metabolism , Viruses/genetics , Viruses/metabolism
15.
Eur J Med Chem ; 211: 113014, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-918799

ABSTRACT

Viruses are obligate intracellular parasites and have evolved to enter the host cell. To gain access they come into contact with the host cell through an initial adhesion, and some viruses from different genus may use heparan sulfate proteoglycans for it. The successful inhibition of this early event of the infection by synthetic molecules has always been an attractive target for medicinal chemists. Numerous reports have yielded insights into the function of compounds based on the dispirotripiperazine scaffold. Analysis suggests that this is a structural requirement for inhibiting the interactions between viruses and cell-surface heparan sulfate proteoglycans, thus preventing virus entry and replication. This review summarizes our current knowledge about the early history of development, synthesis, structure-activity relationships and antiviral evaluation of dispirotripiperazine-based compounds and where they are going in the future.


Subject(s)
Antiviral Agents/pharmacology , Drug Design , Piperazines/pharmacology , Spiro Compounds/pharmacology , Viruses/drug effects , Antiviral Agents/chemistry , Heparan Sulfate Proteoglycans/antagonists & inhibitors , Heparan Sulfate Proteoglycans/metabolism , Molecular Structure , Piperazines/chemistry , Spiro Compounds/chemistry , Viruses/metabolism
16.
Cells ; 10(3)2021 02 24.
Article in English | MEDLINE | ID: covidwho-1147459

ABSTRACT

Intracellular organelles enwrapped in membranes along with a complex network of vesicles trafficking in, out and inside the cellular environment are one of the main features of eukaryotic cells. Given their central role in cell life, compartmentalization and mechanisms allowing their maintenance despite continuous crosstalk among different organelles have been deeply investigated over the past years. Here, we review the multiple functions exerted by the endosomal sorting complex required for transport (ESCRT) machinery in driving membrane remodeling and fission, as well as in repairing physiological and pathological membrane damages. In this way, ESCRT machinery enables different fundamental cellular processes, such as cell cytokinesis, biogenesis of organelles and vesicles, maintenance of nuclear-cytoplasmic compartmentalization, endolysosomal activity. Furthermore, we discuss some examples of how viruses, as obligate intracellular parasites, have evolved to hijack the ESCRT machinery or part of it to execute/optimize their replication cycle/infection. A special emphasis is given to the herpes simplex virus type 1 (HSV-1) interaction with the ESCRT proteins, considering the peculiarities of this interplay and the need for HSV-1 to cross both the nuclear-cytoplasmic and the cytoplasmic-extracellular environment compartmentalization to egress from infected cells.


Subject(s)
Biological Transport/physiology , Cells/metabolism , Endosomal Sorting Complexes Required for Transport/physiology , Viruses/metabolism , Humans
17.
Int J Mol Sci ; 22(4)2021 Feb 16.
Article in English | MEDLINE | ID: covidwho-1139186

ABSTRACT

Bcl-xL represents a family of proteins responsible for the regulation of the intrinsic apoptosis pathway. Due to its anti-apoptotic activity, Bcl-xL co-determines the viability of various virally infected cells. Their survival may determine the effectiveness of viral replication and spread, dynamics of systemic infection, and viral pathogenesis. In this paper, we have reviewed the role of Bcl-xL in the context of host infection by eight different RNA and DNA viruses: hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza A virus (IAV), Epstein-Barr virus (EBV), human T-lymphotropic virus type-1 (HTLV-1), Maraba virus (MRBV), Schmallenberg virus (SBV) and coronavirus (CoV). We have described an influence of viral infection on the intracellular level of Bcl-xL and discussed the impact of Bcl-xL-dependent cell survival control on infection-accompanying pathogenic events such as tissue damage or oncogenesis. We have also presented anti-viral treatment strategies based on the pharmacological regulation of Bcl-xL expression or activity.


Subject(s)
Apoptosis , Virus Diseases/metabolism , bcl-X Protein/metabolism , Animals , Cell Survival , Host-Pathogen Interactions , Humans , Virus Diseases/pathology , Virus Replication , Viruses/metabolism , bcl-X Protein/analysis
18.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Article in English | MEDLINE | ID: covidwho-1125727

ABSTRACT

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.


Subject(s)
Antiviral Agents/metabolism , Hemolytic Agents/metabolism , Insect Proteins/metabolism , Lipids , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Cell Membrane/metabolism , Culicidae , Erythrocytes/drug effects , Fatty Acids, Unsaturated/metabolism , Hemolytic Agents/chemistry , Hemolytic Agents/pharmacology , Humans , Hydrophobic and Hydrophilic Interactions , Insect Proteins/chemistry , Insect Proteins/pharmacology , Ligands , Lipids/chemistry , Protein Binding , Protein Structure, Tertiary , Viral Envelope/metabolism , Viruses/drug effects , Viruses/metabolism
19.
Viruses ; 13(3)2021 02 26.
Article in English | MEDLINE | ID: covidwho-1115433

ABSTRACT

Ubiquitination of proteins is a post-translational modification process with many different cellular functions, including protein stability, immune signaling, antiviral functions and virus replication. While ubiquitination of viral proteins can be used by the host as a defense mechanism by destroying the incoming pathogen, viruses have adapted to take advantage of this cellular process. The ubiquitin system can be hijacked by viruses to enhance various steps of the replication cycle and increase pathogenesis. Emerging viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses like Zika and dengue, as well as highly pathogenic viruses like Ebola and Nipah, have the ability to directly use the ubiquitination process to enhance their viral-replication cycle, and evade immune responses. Some of these mechanisms are conserved among different virus families, especially early during virus entry, providing an opportunity to develop broad-spectrum antivirals. Here, we discuss the mechanisms used by emergent viruses to exploit the host ubiquitin system, with the main focus on the role of ubiquitin in enhancing virus replication.


Subject(s)
Ubiquitin/metabolism , Virus Diseases/metabolism , Virus Replication , Viruses/metabolism , Immune Evasion , Ubiquitination , Viral Proteins/metabolism , Virus Assembly , Virus Diseases/immunology , Virus Diseases/virology , Virus Internalization , Virus Release , Viruses/classification , Viruses/immunology , Viruses/pathogenicity
20.
Cells ; 10(2)2021 02 21.
Article in English | MEDLINE | ID: covidwho-1110386

ABSTRACT

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent histone deacetylases that incorporate complex functions in the mechanisms of cell physiology. Mammals have seven distinct members of the SIRT family (SIRT1-7), which play an important role in a well-maintained network of metabolic pathways that control and adapt the cell to the environment, energy availability and cellular stress. Until recently, very few studies investigated the role of SIRTs in modulating viral infection and progeny. Recent studies have demonstrated that SIRT1 and SIRT2 are promising antiviral targets because of their specific connection to numerous metabolic and regulatory processes affected during infection. In the present review, we summarize some of the recent progress in SIRTs biochemistry and their emerging function as antiviral targets. We also discuss the potential of natural polyphenol-based SIRT modulators to control their functional roles in several diseases including viral infections.


Subject(s)
Metabolic Networks and Pathways , Sirtuins/metabolism , Virus Diseases/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Discovery , Humans , Metabolic Networks and Pathways/drug effects , Models, Molecular , Molecular Targeted Therapy , NAD/metabolism , Sirtuins/analysis , Virus Diseases/drug therapy , Viruses/drug effects , Viruses/metabolism
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