Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections

Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.

Download Full-text

Neural Stem Cells: What Happens When They Go Viral?

Viruses ◽

10.3390/v13081468 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1468

Author(s):

Yashika S. Kamte ◽

Manisha N. Chandwani ◽

Alexa C. Michaels ◽

Lauren A. O’Donnell

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Viral Infections ◽

Wide Spectrum ◽

Cell Types ◽

Developmental Abnormalities ◽

Multipotent Progenitor Cells ◽

The Central Nervous System ◽

Simplex Virus ◽

The Brain

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

Download Full-text

Gene of the month: BECN1

Journal of Clinical Pathology ◽

10.1136/jclinpath-2014-202356 ◽

2014 ◽

Vol 67 (8) ◽

pp. 656-660 ◽

Cited By ~ 38

Author(s):

Sumit Sahni ◽

Angelica M Merlot ◽

Sukriti Krishan ◽

Patric J Jansson ◽

Des R Richardson

Keyword(s):

Neurological Disorders ◽

Viral Infections ◽

Critical Role ◽

Beclin 1 ◽

Biological Processes ◽

Disease States ◽

Binding Partners ◽

Future Drug ◽

Cellular Components ◽

Important Therapeutic Target

The BECN1 gene encodes the Beclin-1 protein, which is a well-established regulator of the autophagic pathway. It is a mammalian orthologue of the ATG6 gene in yeast and was one of the first identified mammalian autophagy-associated genes. Beclin-1 interacts with a number of binding partners in the cell which can lead to either activation (eg, via PI3KC3/Vps34, Ambra 1, UV radiation resistance-associated gene) or inhibition (eg, via Bcl-2, Rubicon) of the autophagic pathway. Apart from its role as a regulator of autophagy, it is also shown to effect important biological processes in the cell such as apoptosis and embryogenesis. Beclin-1 has also been implicated to play a critical role in the pathology of a variety of disease states including cancer, neurological disorders (eg, Alzheimer's disease, Parkinson's disease) and viral infections. Thus, understanding the functions of Beclin-1 and its interactions with other cellular components will aid in its development as an important therapeutic target for future drug development.

Download Full-text

Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00397-19 ◽

2019 ◽

Vol 63 (7) ◽

Cited By ~ 3

Author(s):

Keivan Zandi ◽

Leda Bassit ◽

Franck Amblard ◽

Bryan D. Cox ◽

Pouya Hassandarvish ◽

...

Keyword(s):

Japanese Encephalitis ◽

Viral Infections ◽

Antiviral Agents ◽

Public Health Problem ◽

Nucleoside Analogs ◽

Global Public Health ◽

Direct Acting Antiviral ◽

East And Southeast Asia ◽

Direct Acting ◽

Global Public Health Problem

ABSTRACTDengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from theFlaviviridaefamily. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world’s population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2′-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.

Download Full-text

BPIFB3 interacts with ARFGAP1 and TMED9 to regulate non-canonical autophagy and RNA virus infection

Journal of Cell Science ◽

10.1242/jcs.251835 ◽

2020 ◽

pp. jcs.251835

Author(s):

Azia S. Evans ◽

Nicholas J. Lennemann ◽

Carolyn B. Coyne

Keyword(s):

Mass Spectrometry ◽

Mammalian Cells ◽

Viral Infections ◽

Rna Viruses ◽

Rna Virus ◽

Negative Regulator ◽

Host Factors ◽

Important Negative Regulator ◽

Cellular Components

Autophagy is a degradative cellular pathway that targets cytoplasmic contents and organelles for turnover by the lysosome. Various autophagy pathways play key roles in the clearance of viral infections, and many families of viruses have developed unique methods for avoiding degradation. Some positive stranded RNA viruses, such as enteroviruses and flaviviruses, usurp the autophagic pathway to promote their own replication. We previously identified the endoplasmic reticulum-localized protein BPIFB3 as an important negative regulator of non-canonical autophagy that uniquely impacts the replication of enteroviruses and flaviviruses. Here, we find that many components of the canonical autophagy machinery are not required for BPIFB3 depletion induced autophagy and identify the host factors that facilitate its role in the replication of enteroviruses and flaviviruses. Using proximity-dependent biotinylation (BioID) followed by mass spectrometry, we identify ARFGAP1 and TMED9 as two cellular components that interact with BPIFB3 to regulate autophagy and viral replication. Importantly, our data demonstrate that non-canonical autophagy in mammalian cells can be controlled outside of the traditional pathway regulators and define the role of two proteins in BPIFB3 depletion mediated non-canonical autophagy.

Download Full-text

From the Argonauts Mythological Sailors to the Argonautes RNA-Silencing Navigators: Their Emerging Roles in Human-Cell Pathologies

International Journal of Molecular Sciences ◽

10.3390/ijms21114007 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4007

Author(s):

Vasiliki I. Pantazopoulou ◽

Stella Georgiou ◽

Panos Kakoulidis ◽

Stavroula N. Giannakopoulou ◽

Sofia Tseleni ◽

...

Keyword(s):

Rna Binding ◽

Viral Infections ◽

Rna Binding Proteins ◽

Wide Spectrum ◽

Regulation Of Gene Expression ◽

Human Diseases ◽

Transcriptional Gene Silencing ◽

Nucleotide Polymorphisms ◽

Mrna Targets ◽

Post Transcriptional Gene Silencing

Regulation of gene expression has emerged as a fundamental element of transcript homeostasis. Key effectors in this process are the Argonautes (AGOs), highly specialized RNA-binding proteins (RBPs) that form complexes, such as the RNA-Induced Silencing Complex (RISC). AGOs dictate post-transcriptional gene-silencing by directly loading small RNAs and repressing their mRNA targets through small RNA-sequence complementarity. The four human highly-conserved family-members (AGO1, AGO2, AGO3, and AGO4) demonstrate multi-faceted and versatile roles in transcriptome’s stability, plasticity, and functionality. The post-translational modifications of AGOs in critical amino acid residues, the nucleotide polymorphisms and mutations, and the deregulation of expression and interactions are tightly associated with aberrant activities, which are observed in a wide spectrum of pathologies. Through constantly accumulating information, the AGOs’ fundamental engagement in multiple human diseases has recently emerged. The present review examines new insights into AGO-driven pathology and AGO-deregulation patterns in a variety of diseases such as in viral infections and propagations, autoimmune diseases, cancers, metabolic deficiencies, neuronal disorders, and human infertility. Altogether, AGO seems to be a crucial contributor to pathogenesis and its targeting may serve as a novel and powerful therapeutic tool for the successful management of diverse human diseases in the clinic.

Download Full-text

Macrolide Therapy in Respiratory Viral Infections

Mediators of Inflammation ◽

10.1155/2012/649570 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 32

Author(s):

Jin-Young Min ◽

Yong Ju Jang

Keyword(s):

Influenza Virus ◽

Viral Infection ◽

Viral Infections ◽

Wide Spectrum ◽

Influenza Virus Infection ◽

Respiratory Viral Infection ◽

Rsv Infection ◽

Respiratory Viral Infections ◽

Syncytial Virus ◽

Viral Titers

Background. Macrolides have received considerable attention for their anti-inflammatory and immunomodulatory actions beyond the antibacterial effect. These two properties may ensure some efficacy in a wide spectrum of respiratory viral infections. We aimed to summarize the properties of macrolides and their efficacy in a range of respiratory viral infection.Methods. A search of electronic journal articles through PubMed was performed using combinations of the following keywords including macrolides and respiratory viral infection.Results. Bothin vitroandin vivostudies have provided evidence of their efficacy in respiratory viral infections including rhinovirus (RV), respiratory syncytial virus (RSV), and influenza virus. Much data showed that macrolides reduced viral titers of RV ICAM-1, which is the receptor for RV, and RV infection-induced cytokines including IL-1β, IL-6, IL-8, and TNF-α. Macrolides also reduced the release of proinflammatory cytokines which were induced by RSV infection, viral titers, RNA of RSV replication, and the susceptibility to RSV infection partly through the reduced expression of activated RhoA which is an RSV receptor. Similar effects of macrolides on the influenza virus infection and augmentation of the IL-12 by macrolides which is essential in reducing virus yield were revealed.Conclusion. This paper provides an overview on the properties of macrolides and their efficacy in various respiratory diseases.

Download Full-text

Paediatric viral infections and the blood supply

Microbiology Australia ◽

10.1071/ma05016 ◽

2005 ◽

Vol 26 (1) ◽

pp. 16

Author(s):

Maria E Craig

Keyword(s):

Blood Supply ◽

Common Cold ◽

Viral Infections ◽

Wide Spectrum ◽

Systemic Effects ◽

Normal Part ◽

Mucosal Surfaces ◽

The Common ◽

Main Effects

Viral infections in children frequently exert their main effects at mucosal surfaces, such as the respiratory and gastrointestinal tracts, and do not have significant systemic effects. For example, rhinovirus is found in children with the common cold and asthma; rotavirus is a significant agent in childhood gastroenteritis, and enteroviruses cause a wide spectrum of illness in children and are often asymptomatic. Indeed, experiencing some of these viral infections is considered a normal part of childhood.

Download Full-text

Genome Editing Technologies as Cellular Defense Against Viral Pathogens

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.716344 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yingzi Zhang ◽

Mo Li

Keyword(s):

Infectious Diseases ◽

Genome Editing ◽

Viral Infections ◽

Wide Spectrum ◽

Zinc Finger Nucleases ◽

Transcription Activator ◽

Chronic Infections ◽

Emerging Viruses ◽

Novel Therapy ◽

Viral Pathogens

Viral infectious diseases are significant threats to the welfare of world populations. Besides the widespread acute viral infections (e.g., dengue fever) and chronic infections [e.g., those by the human immunodeficiency virus (HIV) and hepatitis B virus (HBV)], emerging viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose great challenges to the world. Genome editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) proteins, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), have played essential roles in the study of new treatment for viral infectious diseases in cell lines, animal models, and clinical trials. Genome editing tools have been used to eliminate latent infections and provide resistance to new infections. Increasing evidence has shown that genome editing-based antiviral strategy is simple to design and can be quickly adapted to combat infections by a wide spectrum of viral pathogens, including the emerging coronaviruses. Here we review the development and applications of genome editing technologies for preventing or eliminating infections caused by HIV, HBV, HPV, HSV, and SARS-CoV-2, and discuss how the latest advances could enlighten further development of genome editing into a novel therapy for viral infectious diseases.

Download Full-text

Role of Virus-Related Chronic Inflammation and Mechanisms of Cancer Immune-Suppression in Pathogenesis and Progression of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13174387 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4387

Author(s):

Melissa Borgia ◽

Michele Dal Bo ◽

Giuseppe Toffoli

Keyword(s):

Hepatocellular Carcinoma ◽

Viral Infections ◽

Hepatitis Virus ◽

Immune Surveillance ◽

Significant Proportion ◽

Intrinsic Factors ◽

Direct Acting Antiviral ◽

Tumor Onset ◽

Immunosuppressive Tumor Microenvironment ◽

Direct Acting

Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with.

Download Full-text

SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21165707 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5707 ◽

Cited By ~ 8

Author(s):

Rolando Cannalire ◽

Irina Stefanelli ◽

Carmen Cerchia ◽

Andrea R. Beccari ◽

Sveva Pelliccia ◽

...

Keyword(s):

Small Molecules ◽

Viral Entry ◽

Viral Infections ◽

Host Factors ◽

Host Cells ◽

S Protein ◽

Entry Inhibitors ◽

Heptad Repeats ◽

Direct Acting ◽

Complementary Strategy

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.

Download Full-text