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Emerging Microbes & Infections Dec 2023Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain-Barré syndrome in adults, and microcephaly in...
Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain-Barré syndrome in adults, and microcephaly in newborns). There are currently no specific therapy or vaccine options available to prevent ZIKV infections. Temporal gene expression profiles of ZIKV-infected human brain microvascular endothelial cells (HBMECs) were used in this study to identify genes essential for viral replication. These genes were then used to identify novel anti-ZIKV agents and validated in publicly available data and functional wet-lab experiments. Here, we found that ZIKV effectively evaded activation of immune response-related genes and completely reprogrammed cellular transcriptional architectures. Knockdown of genes, which gradually upregulated during viral infection but showed distinct expression patterns between ZIKV- and mock infection, discovered novel proviral and antiviral factors. One-third of the 74 drugs found through signature-based drug repositioning and cross-reference with the Drug Gene Interaction Database (DGIdb) were known anti-ZIKV agents. In cellular assays, two promising antiviral candidates (Luminespib/NVP-AUY922, L-161982) were found to reduce viral replication without causing cell toxicity. Overall, our time-series transcriptome-based methods offer a novel and feasible strategy for antiviral drug discovery. Our strategies, which combine conventional and data-driven analysis, can be extended for other pathogens causing pandemics in the future.
Topics: Infant, Newborn; Humans; Zika Virus; Transcriptome; Endothelial Cells; Zika Virus Infection; Antiviral Agents; Virus Replication
PubMed: 36715162
DOI: 10.1080/22221751.2023.2174777 -
International Journal of Infectious... Dec 2023After the third year of the COVID-19 pandemic, most of the severe COVID-19 burden falls upon immunocompromised patients who cannot mount an endogenous immune response... (Review)
Review
OBJECTIVES
After the third year of the COVID-19 pandemic, most of the severe COVID-19 burden falls upon immunocompromised patients who cannot mount an endogenous immune response after both vaccination and/or natural infection. They also experience persistent SARS-CoV-2 infection with high viral loads often unsuccessfully managed by the standard antiviral monotherapy regimen initially validated for treatment of COVID-19 immunocompetent patients, only. The off-label prescription of such monotherapy regimens in immunocompromised patients is likely to drive the emergence of treatment-related immune escape, relapses, excess morbidity, and mortality from both COVID-19 and delayed treatment of the underlying disorders. A possible treatment approach to mitigate such consequence is based on combined antiviral therapies.
METHODS
We searched PubMed for case reports, case series and clinical trials reporting the usage of combined antiviral therapies for COVID-19.
RESULTS
In this narrative review, we show that combinations of either small molecule antivirals or small molecule antiviral plus passive immunotherapies are safe and effective in small cohorts reported so far.
CONCLUSION
Considering the progressive loss of efficacy of all authorized anti-spike monoclonal antibodies, promising regimen options are reserved to combinations of small molecule antivirals and COVID-19 convalescent plasma from vaccinated donors.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; COVID-19 Serotherapy; Antiviral Agents; Immunocompromised Host
PubMed: 37778409
DOI: 10.1016/j.ijid.2023.09.021 -
Handbook of Experimental Pharmacology 2009Viruses are obligatory intracellular parasites, whose replication depends on pathways and functions of the host cell. Consequently, it is difficult to define... (Review)
Review
Viruses are obligatory intracellular parasites, whose replication depends on pathways and functions of the host cell. Consequently, it is difficult to define virus-specific functions as suitable targets for anti-infective therapy. However, significant progress has been made in the past 50 years towards the development of effective and specific antivirals. In particular, human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, which cause chronic infections affecting millions of individuals world-wide, are a major focus of antiviral research. Initially, antivirals were mainly directed against virus-specific enzymes; more recently, drugs inhibiting the steps of virus entry or release have been developed. Rational approaches towards drug development, based on information about structure and function of viral proteins and molecular mechanisms of virus-host interactions, have become increasingly successful. Novel strategies currently explored in basic research or preclinical studies include approaches targeting host factors important for virus replication, the exploitation of the innate immune response system as well as the use of gene silencing strategies aimed at interfering with viral gene expression. Today, a number of effective virostatics targeting various viral replication steps are approved for treatment of important viral diseases. However, the use of these drugs is limited by the rapid development of antiviral resistance, which represents a central problem of current antiviral therapy.
Topics: Animals; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Virus Replication; Viruses
PubMed: 19048195
DOI: 10.1007/978-3-540-79086-0_1 -
European Journal of Medicinal Chemistry Sep 2020Viruses continue to be a major threat to human health. In the last century, pandemics occurred and resulted in significant mortality and morbidity. Natural products have... (Review)
Review
Viruses continue to be a major threat to human health. In the last century, pandemics occurred and resulted in significant mortality and morbidity. Natural products have been largely screened as source of inspiration for new antiviral agents. Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids present a wide structural diversity and mediate a great number of biological responses relevant for human health. However, whilst the antiviral activity of resveratrol has been extensively studied, little is known about the efficacy of its monomeric and oligomeric derivatives. The purpose of this review is to provide an overview of the achievements in this field, with particular emphasis on the source, chemical structures and the mechanism of action of resveratrol-derived stilbenoids against the most challenging viruses. The collected results highlight the therapeutic versatility of stilbene-containing compounds and provide a prospective insight into their potential development as antiviral agents.
Topics: Antiviral Agents; Biological Products; Microbial Sensitivity Tests; Molecular Structure; Stilbenes; Viruses
PubMed: 32652408
DOI: 10.1016/j.ejmech.2020.112541 -
Frontiers in Cellular and Infection... 2022Probiotics exert a variety of beneficial effects, including maintaining homeostasis and the balance of intestinal microorganisms, activating the immune system, and... (Review)
Review
Probiotics exert a variety of beneficial effects, including maintaining homeostasis and the balance of intestinal microorganisms, activating the immune system, and regulating immune responses. Due to the beneficial effects of probiotics, a wide range of probiotics have been developed as probiotic agents for animal and human health. Viral diseases cause serious economic losses to the livestock every year and remain a great challenge for animals. Moreover, strategies for the prevention and control of viral diseases are limited. Viruses enter the host through the skin and mucosal surface, in which are colonized by hundreds of millions of microorganisms. The antiviral effects of probiotics have been proved, including modulation of chemical, microbial, physical, and immune barriers through various probiotics, probiotic metabolites, and host signaling pathways. It is of great significance yet far from enough to elucidate the antiviral mechanisms of probiotics. The major interest of this review is to discuss the antiviral effects and underlying mechanisms of probiotics and to provide targets for the development of novel antivirals.
Topics: Animals; Antiviral Agents; Immune System; Intestines; Probiotics; Viruses
PubMed: 35734576
DOI: 10.3389/fcimb.2022.928050 -
Neuroimmunomodulation 2023The assumption of the pineal hormone melatonin as a therapeutic use for COVID-19-affected people seems promising. Its intake has shown significant improvement in the... (Review)
Review
The assumption of the pineal hormone melatonin as a therapeutic use for COVID-19-affected people seems promising. Its intake has shown significant improvement in the patients' conditions. Higher melatonin titers in children may provide a protective shield against this disease. The hormone melatonin works as an anti-inflammatory, antioxidant, immunomodulator, and strategically slows down the cytokine release which is observed in the COVID-19 disease, thereby improving the overall health of afflicted patients. The medical community is expected shortly to use remedial attributes like anti-inflammatory, antioxidant, antivirals, etc., of melatonin in the successful prevention and cure of COVID-19 morbidity. Thus, the administration of melatonin seems auspicious in the cure and prevention of this COVID-19 fatality. Moreover, melatonin does not seem to reduce the efficiency of approved vaccines against the SARS-CoV-2 virus. Melatonin increases the production of inflammatory cytokines and Th1 and enhances both humoral and cell-mediated responses. Through the enhanced humoral immunity, melatonin exhibits antiviral activities by suppressing multiple inflammatory products such as IL-6, IL1β, and tumor necrosis factor α, which are immediately released during lung injury of severe COVID-19. Hence, the novel use of melatonin along with other antivirals as an early treatment option against COVID-19 infection is suggested. Here, we have chalked out the invasion mechanisms and appropriate implications of the latest findings concerned with melatonin against the virus SARS-CoV-2. Nevertheless, within the setting of a clinical intervention, the promising compounds must go through a series of studies before their recommendation. In the clinical field, this is done in a time-ordered sequence, in line with the phase label affixed to proper protocol of trials: phase I-phase II and the final phase III. Nevertheless, while medical recommendations can only be made on the basis of reassuring evidence, there are still three issues worth considering before implementation: representativeness, validity, and lastly generalizability.
Topics: Child; Humans; COVID-19; Melatonin; SARS-CoV-2; Antioxidants; Antiviral Agents; Anti-Inflammatory Agents
PubMed: 37336193
DOI: 10.1159/000531550 -
International Journal of Molecular... Sep 2022The innate immune system facilitates defense mechanisms against pathogen invasion and cell damage. Toll-like receptors (TLRs) assist in the activation of the innate... (Review)
Review
The innate immune system facilitates defense mechanisms against pathogen invasion and cell damage. Toll-like receptors (TLRs) assist in the activation of the innate immune system by binding to pathogenic ligands. This leads to the generation of intracellular signaling cascades including the biosynthesis of molecular mediators. TLRs on cell membranes are adept at recognizing viral components. Viruses can modulate the innate immune response with the help of proteins and RNAs that downregulate or upregulate the expression of various TLRs. In the case of COVID-19, molecular modulators such as type 1 interferons interfere with signaling pathways in the host cells, leading to an inflammatory response. Coronaviruses are responsible for an enhanced immune signature of inflammatory chemokines and cytokines. TLRs have been employed as therapeutic agents in viral infections as numerous antiviral Food and Drug Administration-approved drugs are TLR agonists. This review highlights the therapeutic approaches associated with SARS-CoV-2 and the TLRs involved in COVID-19 infection.
Topics: Antiviral Agents; Chemokines; Cytokines; Humans; Immunity, Innate; Interferon Type I; Ligands; SARS-CoV-2; Toll-Like Receptors; COVID-19 Drug Treatment
PubMed: 36142620
DOI: 10.3390/ijms231810716 -
Cellular and Molecular Gastroenterology... 2022The persistence of viral covalently closed circular DNA (cccDNA) is the major obstacle for antiviral treatment against hepatitis B virus (HBV). Basic and translational...
BACKGROUND AND AIMS
The persistence of viral covalently closed circular DNA (cccDNA) is the major obstacle for antiviral treatment against hepatitis B virus (HBV). Basic and translational studies are largely hampered due to the lack of feasible small animal models to support HBV cccDNA formation. The aim of this study is to establish a novel mouse model harboring cccDNA.
METHODS
An adeno-associated virus (AAV) vector carrying a replication-deficient HBV1.04-fold genome (AAV-HBV1.04) was constructed. The linear HBV genome starts from nucleotide 403 and ends at 538, which results in the splitting of HBV surface and polymerase genes. Different HBV replication markers were evaluated for AAV-HBV1.04 plasmid-transfected cells, the AAV-HBV1.04 viral vector-transduced cells, and mice injected with the AAV-HBV1.04 viral vector.
RESULTS
Compared with the previously reported AAV-HBV1.2 construct, direct transfection of AAV-HBV1.04 plasmid failed to produce hepatitis B surface antigen and progeny virus. Interestingly, AAV-HBV1.04 viral vector transduction could result in the formation of cccDNA and the production of all HBV replication markers in vitro and in vivo. The formation of cccDNA could be blocked by ATR (ataxia-telangiectasia and Rad3-related protein) inhibitors but not HBV reverse transcription inhibitor or capsid inhibitors. The AAV-HBV1.04 mouse supported long-term HBV replication and responded to antiviral treatments.
CONCLUSIONS
This AAV-HBV1.04 mouse model can support HBV cccDNA formation through ATR-mediated DNA damage response. The de novo formed cccDNA but not the parental AAV vector can lead to the production of hepatitis B surface antigen and HBV progeny. This model will provide a unique platform for studying HBV cccDNA and developing novel antivirals against HBV infection.
Topics: Animals; Antiviral Agents; DNA, Circular; DNA, Viral; Dependovirus; Disease Models, Animal; Hepatitis B Surface Antigens; Hepatitis B virus; Mice; Virus Replication
PubMed: 34896285
DOI: 10.1016/j.jcmgh.2021.11.011 -
Journal of Translational Medicine May 2014Chronic hepatitis B and C are the leading causes of liver disease and liver transplantation worldwide. Ability to mount an effective immune response against both HBV and... (Review)
Review
Chronic hepatitis B and C are the leading causes of liver disease and liver transplantation worldwide. Ability to mount an effective immune response against both HBV and HCV is associated with spontaneous clearance of both infections, while an inability to do so leads to chronicity of both infections. To mount an effective immune response, both innate and adaptive immune responses must work in tandem. Hence, developing protective immunity to hepatitis viruses is an important goal in order to reduce the global burden of these two infections and prevent development of long-term complications. In this regard, the initial interactions between the pathogen and immune system are pivotal in determining the effectiveness of immune response and subsequent elimination of pathogens. Toll-like receptors (TLRs) are important regulators of innate and adaptive immune responses to various pathogens and are often involved in initiating and augmenting effective antiviral immunity. Immune-based therapeutic strategies that specifically induce type I interferon responses are associated with functional cure for both chronic HBV and HCV infections. Precisely, TLR7 stimulation mediates an endogenous type I interferon response, which is critical in development of a broad, effective and protective immunity against hepatitis viruses. This review focuses on anti-viral strategies that involve targeting TLR7 that may lead to development of protective immunity and eradication of hepatitis B.
Topics: Antiviral Agents; Hepatitis B; Hepatitis C; Humans; Toll-Like Receptor 7
PubMed: 24884741
DOI: 10.1186/1479-5876-12-129 -
International Journal of Molecular... May 2023Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and... (Review)
Review
Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs' susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The are viruses with the largest genome among the RNA viruses. - (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.
Topics: Animals; Interferons; SARS-CoV-2; COVID-19; Antiviral Agents; Interferon Type I; Cytokines; Immunity, Innate; Immune Evasion
PubMed: 37298304
DOI: 10.3390/ijms24119353