-
Frontiers in Immunology 2019Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections... (Review)
Review
Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections remains limited and is challenged by the virus itself. While vaccination is the preferred intervention strategy against influenza, its efficacy is reduced in the elderly and infants who are most susceptible to severe and/or fatal infections. In addition, antigenic variation of IAV complicates the production of efficacious vaccines. Similarly, effectiveness of currently used antiviral drugs is jeopardized by the development of resistance to these drugs. Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. While host-factors have long been recognized as attractive therapeutic candidates against other viruses, only recently they have been targeted for development as IAV antivirals. Future strategies to combat IAV infections will most likely include approaches that alter host-virus interactions on the one hand or dampen harmful host immune responses on the other, with the use of biological response modifiers (BRMs). In principle, BRMs are biologically active agents including antibodies, small peptides, and/or other (small) molecules that can influence the immune response. BRMs are already being used in the clinic to treat malignancies and autoimmune diseases. Repurposing such agents would allow for accelerated use against severe and potentially fatal IAV infections. In this review, we will address the potential therapeutic use of different BRM classes to modulate the immune response induced after IAV infections.
Topics: Animals; Antiviral Agents; Host-Pathogen Interactions; Humans; Immunologic Factors; Immunomodulation; Influenza A virus; Influenza, Human; Treatment Outcome
PubMed: 31031778
DOI: 10.3389/fimmu.2019.00809 -
Journal of Viral Hepatitis Mar 2017Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of... (Review)
Review
Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV-NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.
Topics: Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Viral Nonstructural Proteins; Virus Replication
PubMed: 27925362
DOI: 10.1111/jvh.12657 -
Cell Reports Jul 2022Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in... (Review)
Review
Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in response to viral infections. IFNs are powerful antivirals, whereas defects in their function or induction lead to impaired resistance to virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. IFN production needs to be controlled, because sustained IFN production can also have detrimental effects on disease outcome. As such, pDCs are likely important for acute antiviral protection against SARS-CoV-2 infection but could potentially also contribute to chronic IFN levels. Here, we provide a historical overview of pDC biology and summarize existing literature addressing their involvement and importance during viral infections of the airways. Furthermore, we outline recent reports focused on the potential role of pDCs during SARS-CoV-2 infection, as well as the potential for this cellular subset to impact COVID-19 disease outcome.
Topics: Antiviral Agents; COVID-19; Dendritic Cells; Humans; Interferon Type I; SARS-CoV-2
PubMed: 35858624
DOI: 10.1016/j.celrep.2022.111148 -
European Journal of Medicinal Chemistry Mar 2018Hepatitis B virus (HBV) infections affect about 240 million patients worldwide and increase the risk of liver cirrhosis and hepatocellular carcinoma. It is estimated... (Review)
Review
Hepatitis B virus (HBV) infections affect about 240 million patients worldwide and increase the risk of liver cirrhosis and hepatocellular carcinoma. It is estimated that about 686 thousand people died annually of liver damage resulted from HBV infections. At present, two classes of antiviral drugs have been approved by the Food and Drug Administration (FDA) for the treatment of hepatitis B, immunomodulators (interferon [IFN]-a and pegylated-interferon [PEG-IFN]-a) and nucleos(t)ide analogs (lamivudine, telbivudine, adefovir, tenofovir [TDF], and entecavir [ETV]). However, it still remains a daunting challenge for curing HBV, because of the low sustained response rates (20-30%) and many side effects of IFN and peg-IFN. Although nucleoside analogues are well tolerated and exhibit an early and potent antiviral effect, the selection of resistant mutants and nephrotoxicity during long-term therapy limit their use. Here, we focus on summarizing the currently approved anti-HBV drugs and characterization of novel HBV inhibitors and analysing their structures, targets, anti-HBV effects and mechanisms of action, which may shed new light on the discovery of small compounds as potential anti-HBV drugs for treatment of HBV.
Topics: Antiviral Agents; Hepatitis B virus; Microbial Sensitivity Tests; Molecular Conformation
PubMed: 29438889
DOI: 10.1016/j.ejmech.2018.02.001 -
The Interplay of Genital Herpes with Cellular Processes: A Pathogenesis and Therapeutic Perspective.Viruses Oct 2023Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular... (Review)
Review
Genital herpes, primarily caused by herpes simplex virus-2 (HSV-2), remains a pressing global health concern. Its remarkable ability to intertwine with cellular processes, from harnessing host machinery for replication to subverting antiviral defenses like autophagy and programmed cell death, exemplifies the intricate interplay at the heart of its pathogenesis. While the biomedical community has extensively researched antiviral interventions, the efficiency of these strategies in managing HSV-2 remains suboptimal. Recognizing this, attention has shifted toward leveraging host cellular components to regulate HSV-2 replication and influence the cell cycle. Furthermore, innovative interventional strategies-including drug repurposing, microbivacs, connecting the host microbiome, and exploiting natural secondary metabolites-are emerging as potential game changers. This review summarizes the key steps in HSV-2 pathogenesis and newly discovered cellular interactions, presenting the latest developments in the field, highlighting existing challenges, and offering a fresh perspective on HSV-2's pathogenesis and the potential avenues for its treatment by targeting cellular proteins and pathways.
Topics: Humans; Herpes Genitalis; Herpesvirus 2, Human; Autophagy; Antiviral Agents; Herpes Simplex
PubMed: 38005873
DOI: 10.3390/v15112195 -
Cold Spring Harbor Perspectives in... Apr 2021In the last few years, several new direct-acting influenza antivirals have been licensed, and others have advanced in clinical development. The increasing diversity of... (Review)
Review
In the last few years, several new direct-acting influenza antivirals have been licensed, and others have advanced in clinical development. The increasing diversity of antiviral classes should allow an adequate public health response should a resistant virus to one agent or class widely circulate. One new antiviral, baloxavir marboxil, has been approved in the United States for treatment of influenza in those at high risk of developing influenza-related complications. Except for intravenous zanamivir in European Union countries, no antivirals have been licensed specifically for the indication of severe influenza or hospitalized influenza. This review addresses recent clinical developments involving selected polymerase inhibitors, neuraminidase inhibitors, antibody-based therapeutics, and host-directed therapies. There are many knowledge gaps for most of these agents because some data are not published and multiple pivotal studies are in progress at present. This review also considers important clinical research issues, including regulatory pathways, study designs, endpoints, and target populations encountered during the clinical development of novel therapeutics.
Topics: Antiviral Agents; Drug Development; Drug Resistance, Viral; Humans; Influenza, Human; Nucleic Acid Synthesis Inhibitors
PubMed: 32041763
DOI: 10.1101/cshperspect.a038463 -
Nature Communications Nov 2023Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic...
Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.
Topics: Poxviridae; Cytoplasm; Nucleotidyltransferases; Antiviral Agents; Nucleic Acids
PubMed: 38036506
DOI: 10.1038/s41467-023-43635-y -
The Journal of Infection Jun 2015Respiratory syncytial virus (RSV) remains a significant cause of morbidity and mortality in infants, immunocompromised patients and the elderly. Despite the high disease... (Review)
Review
Respiratory syncytial virus (RSV) remains a significant cause of morbidity and mortality in infants, immunocompromised patients and the elderly. Despite the high disease burden, an effective vaccine or specific therapy are lacking which is largely due to our limited understanding of the immune response to RSV and how it relates to clinical disease severity. Current treatment for RSV remains largely supportive and RSV-specific options for prophylaxis and/or treatment are limited to palivizumab and ribavirin. There are a number of promising compounds currently under development, including new monoclonal antibodies and small molecules. These newer antivirals have the potential to impact both the prevention and treatment of RSV disease in the main target populations.
Topics: Antibodies, Monoclonal; Antiviral Agents; Child; Humans; Infant; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses
PubMed: 25922289
DOI: 10.1016/j.jinf.2015.04.025 -
Letters in Applied Microbiology Sep 2022There is a need for new effective antivirals, particularly in response to the development of antiviral drug resistance and emerging RNA viruses such as SARS-CoV-2.... (Review)
Review
There is a need for new effective antivirals, particularly in response to the development of antiviral drug resistance and emerging RNA viruses such as SARS-CoV-2. Plants are a significant source of structurally diverse bioactive compounds for drug discovery suggesting that plant-derived natural products could be developed as antiviral agents. This article reviews the antiviral activity of plant-derived natural products against RNA viruses, with a focus on compounds targeting specific stages of the viral life cycle. A range of plant extracts and compounds have been identified with antiviral activity, often against multiple virus families suggesting they may be useful as broad-spectrum antiviral agents. The antiviral mechanism of action of many of these phytochemicals is not fully understood and there are limited studies and clinical trials demonstrating their efficacy and toxicity in vivo. Further research is needed to evaluate the therapeutic potential of plant-derived natural products as antiviral agents.
Topics: Animals; Antiviral Agents; Biological Products; Life Cycle Stages; Plant Extracts; RNA Viruses; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34953146
DOI: 10.1111/lam.13637 -
Postepy Higieny I Medycyny... Sep 2015Influenza virus neuraminidase inhibitors (NAIs), including oseltamivir, zanamivir and peramivir, are important antivirals for the treatment and prophylaxis of influenza.... (Review)
Review
Influenza virus neuraminidase inhibitors (NAIs), including oseltamivir, zanamivir and peramivir, are important antivirals for the treatment and prophylaxis of influenza. Increasing use of NAIs brings into focus the risk of drug resistance. The problem of resistance is of high clinical and epidemiological importance. There are generally three levels of antiviral resistance according to the way that resistance can be detected or inferred: genotypic, phenotypic and clinical resistance. Recently the problem of resistance to NAIs, although still rare (<2% of influenza isolates), has been rising. It should be underlined that NAI resistance in influenza viruses is relative, and despite its presence patients with resistant viruses may still benefit from receiving NAIs. The clinical resistance and the response to treatment with antivirals remain the most important proof of antiviral effectiveness. Currently, there has not been observed cross-resistance between oseltamivir and zanamivir, which may be a consequence of the number of given doses, differences in drug structure and duration of the drug concentrations in the site of infection. Early treatment with appropriate doses of NAI is necessary to minimize the likelihood of a resistant virus arising.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Drug Resistance, Viral; Enzyme Inhibitors; Female; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Neuraminidase; Oseltamivir; Young Adult; Zanamivir
PubMed: 26400894
DOI: No ID Found