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Microbiology Spectrum Aug 2023The emergence or reemergence of viruses pose a substantial threat and challenge to the world population, livestock, and wildlife. However, the landscape of antiviral...
The emergence or reemergence of viruses pose a substantial threat and challenge to the world population, livestock, and wildlife. However, the landscape of antiviral agents either for human or animal viral diseases is still underdeveloped. The far tougher actuality is the case that there are no approved antiviral drugs in the aquaculture industry, although there are diverse viral pathogens. In this study, using a novel epithelial cell line derived from the brain of Micropterus salmoides (MSBr), inflammation and oxidative stress were found to implicate the major pathophysiology of rhabdovirus (MSRV) through transcriptome analysis and biochemical tests. Elevated levels of proinflammatory cytokines (interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and gamma interferon [IFN-γ]) and accumulated contents of reactive oxygen species (ROS) as well as biomarkers of oxidative damage (protein carbonyl and 8-OHdG) were observed after MSRV infection in the MSBr cells. Mangiferin or taurine dampened MSRV-induced inflammation and rescued the oxidative stress and, thus, inhibited the replication of MSRV in the MSBr cells with 50% effective concentration (EC) values of 6.77 μg/mL and 8.02 μg/mL, respectively. Further, mangiferin or taurine hampered the activation of NF-κB1 and the NF-κB1 promoter as well as the increase of phosphorylated NF-κB (p65) protein level induced by MSRV infection, indicating their antiviral mechanism by suppressing NF-κB signaling. These findings exemplify a practice approach, aiming to dampen and redirect inflammatory responses, to develop broad-spectrum antivirals. Aquaculture now provides almost half of all fish for human food in 2021 and plays a significant role in eliminating hunger, promoting health, and reducing poverty. There are diverse viral pathogens that decrease production in aquaculture. We developed a novel epithelial cell line derived from the brain of , which can be used for virus isolation, gene expressing, and drug screening. In this study, we focus on rhabdovirus (MSRV) and revealed its pathophysiology of inflammation and oxidative stress. Aiming to dampen and redirect inflammatory responses, mangiferin or taurine exhibited their antiviral capability by suppressing NF-κB signaling. Our findings exemplify a practice approach to develop broad-spectrum antivirals by dampening and redirecting inflammatory responses.
Topics: Animals; Humans; NF-kappa B; Taurine; Rhabdoviridae; Inflammation; Bass; Antiviral Agents
PubMed: 37255471
DOI: 10.1128/spectrum.05146-22 -
Drug Design, Development and Therapy 2022The aim of this report is to review the literature and shed light on the uncertainties surrounding the use of antiviral agents in general and remdesivir in COVID-19... (Review)
Review
The aim of this report is to review the literature and shed light on the uncertainties surrounding the use of antiviral agents in general and remdesivir in COVID-19 patients. This review evaluated a battery of antiviral compounds and their effectiveness in the treatment of COVID-19 since the beginning of the pandemic. Remdesivir is the only antiviral approved by the EMA and FDA for the treatment of SARS-CoV-2 infection. This work extensively reviews remdesivir data generated from clinical trials and observational studies, paying attention to the most recent data, and focusing on outcomes to give readers a more comprehensive understanding of the results. This review also discusses the recommendations issued by official bodies during the pandemic in the light of the current knowledge. The use of remdesivir in the treatment of SARS-CoV-2 infection is justified because a virus is the causative agent that triggers the inflammatory responses and its consequences. More trials are needed to improve the management of this disease.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 35370401
DOI: 10.2147/DDDT.S356951 -
Pharmacological Reports : PR Jun 2021The SARS-CoV-2 has affected millions worldwide and has posed an immediate need for effective pharmacological interventions. Ever since the outbreak was declared, the... (Review)
Review
The SARS-CoV-2 has affected millions worldwide and has posed an immediate need for effective pharmacological interventions. Ever since the outbreak was declared, the medical fraternity across the world is facing a unique situation of offering assistance and simultaneously generating reliable data with high-quality evidence to extend the scope of finding a treatment. With no proven vaccine or other interventions available hitherto, there is a frenzied urgency of sharing preliminary data from laboratories and trials to shape a global response against the virus. Several clinical trials with investigational and approved repurposed therapeutics have shown promising results. This review aims to compile the information of the reported molecules approved for emergency use and those under clinical trials and still others with good results in the studies conducted so far. Being an RNA virus, SARS-CoV-2 is prone to mutation; thus, the possibility of gaining resistance to available drugs is high. Consequently, a cocktail therapy based on drug interaction with different stages of its replicative cycle is desirable to reduce the chances of evolving drug resistance. Since this virus encodes several proteins, including 16 nonstructural and 4 structural proteins, this review also offers an insight into potential drug targets within SARS-CoV-2.
Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33389724
DOI: 10.1007/s43440-020-00204-0 -
Journal of Medicinal Chemistry Jun 2022SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral... (Review)
Review
SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL) mediates the cleavage of viral polyprotein and modulates the host's innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL inhibitors to the clinic.
Topics: Antiviral Agents; Coronavirus Papain-Like Proteases; Humans; Pandemics; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35620927
DOI: 10.1021/acs.jmedchem.2c00303 -
American Journal of Physiology. Lung... Aug 2023Bronchoconstriction is the main physiological event in asthma, which leads to worsened clinical symptoms and generates mechanical stress within the airways. Virus...
Bronchoconstriction is the main physiological event in asthma, which leads to worsened clinical symptoms and generates mechanical stress within the airways. Virus infection is the primary cause of exacerbations in people with asthma, however, the impact that bronchoconstriction itself on host antiviral responses and viral replication is currently not well understood. Here we demonstrate how mechanical forces generated during bronchoconstriction may suppress antiviral responses at the airway epithelium without any difference in viral replication. Primary bronchial epithelial cells from donors with asthma were differentiated at the air-liquid interface. Differentiated cells were apically compressed (30 cmHO) for 10 min every hour for 4 days to mimic bronchoconstriction. Two asthma disease models were developed with the application of compression, either before ("poor asthma control model," = 7) or following ("exacerbation model," = 4) rhinovirus (RV) infection. Samples were collected at 0, 24, 48, 72, and 96 h postinfection (hpi). Viral RNA, interferon (IFN)-β, IFN-λ, and host defense antiviral peptide gene expressions were measured along with IFN-β, IFN-λ, TGF-β, interleukin-6 (IL-6), and IL-8 protein expression. Apical compression significantly suppressed RV-induced IFN-β protein from 48 hpi and IFN-λ from 72 hpi in the poor asthma control model. There was a nonsignificant reduction of both IFN-β and IFN-λ proteins from 48 hpi in the exacerbation model. Despite reductions in antiviral proteins, there was no significant change in viral replication in either model. Compressive stress mimicking bronchoconstriction inhibits antiviral innate immune responses from asthmatic airway epithelial cells when applied before RV infection. Bronchoconstriction is the main physiological event in asthma, which leads to worsened clinical symptoms and generates mechanical stress within the airways. Virus infection is the primary cause of exacerbations in people with asthma, however, the impact of bronchoconstriction on host antiviral responses and viral replication is unknown. We developed two disease models, in vitro, and found suppressed IFN response from cells following the application of compression and RV-A1 infection. This explains why people with asthma have deficient IFN response.
Topics: Humans; Rhinovirus; Immunity, Innate; Asthma; Antiviral Agents; Epithelial Cells; Picornaviridae Infections
PubMed: 37280545
DOI: 10.1152/ajplung.00074.2022 -
Population Health Management Dec 2022Oral antivirals for COVID-19 can be game changers in low- and middle-income countries (LMICs). Challenges that may hinder current and future oral antiviral rollouts span...
Oral antivirals for COVID-19 can be game changers in low- and middle-income countries (LMICs). Challenges that may hinder current and future oral antiviral rollouts span use in special populations, drug-drug and herb-drug interactions, adverse events, development of resistance, black markets, and equity in access and prescribing. Future antivirals may address some of these barriers; however, health systems around the world should be equipped to receive and administer COVID-19 oral antivirals. Improvements in manufacturing capacity, community engagement, capacity for testing and linkage to care, and systems for surveillance and safety monitoring could "change the game" for LMICs, irrespective of any specific antiviral drug. Investments in health care infrastructure can promote resilience, not only for COVID-19 but also for future local and global health crises.
Topics: Humans; COVID-19; Antiviral Agents; Global Health; Developing Countries
PubMed: 36315439
DOI: 10.1089/pop.2022.0171 -
Journal of Hepatology Feb 2024Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better...
BACKGROUND & AIMS
Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better characterization of virus-host interactions is required to develop new therapeutic strategies.
METHODS
Using loss-of-function strategies, we validated the unexpected proviral activity of Janus kinase 1 (JAK1) - a key player in innate immunity - in the HDV life cycle and determined its mechanism of action on HDV through various functional analyses including co-immunoprecipitation assays.
RESULTS
We confirmed the key role of JAK1 kinase activity in HDV infection. Moreover, our results suggest that JAK1 inhibition is associated with a modulation of ERK1/2 activation and S-HDAg phosphorylation, which is crucial for viral replication. Finally, we showed that FDA-approved JAK1-specific inhibitors are efficient antivirals in relevant in vitro models including primary human hepatocytes.
CONCLUSIONS
Taken together, we uncovered JAK1 as a key host factor for HDV replication and a potential target for new antiviral treatment.
IMPACT AND IMPLICATIONS
Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. As no curative treatment is currently available, new therapeutic strategies based on host-targeting agents are urgently needed. Here, using loss-of-function strategies, we uncover an unexpected interaction between JAK1, a major player in the innate antiviral response, and HDV infection. We demonstrated that JAK1 kinase activity is crucial for both the phosphorylation of the delta antigen and the replication of the virus. By demonstrating the antiviral potential of several FDA-approved JAK1 inhibitors, our results could pave the way for the development of innovative therapeutic strategies to tackle this global health threat.
Topics: Humans; Hepatitis Delta Virus; Janus Kinase 1; Hepatitis B virus; Hepatitis D, Chronic; Antiviral Agents; Virus Replication
PubMed: 37925078
DOI: 10.1016/j.jhep.2023.10.030 -
Microbiology Spectrum Aug 2022In this study, we use electric cell-substrate impedance sensing (ECIS), an established cell-based electrical impedance (CEI) technology, to decipher the kinetic...
In this study, we use electric cell-substrate impedance sensing (ECIS), an established cell-based electrical impedance (CEI) technology, to decipher the kinetic cytopathic effect (CPE) induced by Zika virus (ZIKV) in susceptible human A549 lung epithelial cells and to evaluate several classes of compounds with reported antiviral activity (two entry inhibitors and two replication inhibitors). To validate the assay, we compare the results with those obtained with more traditional methods based on cell viability and viral yield readouts. We demonstrate that CEI can detect viral infection in a sensitive manner and can be used to determine antiviral potency. Moreover, CEI has multiple benefits compared to conventional assays: the technique is less laborious and better at visualizing the dynamic antiviral activity profile of the compounds, while also it has the ability to determine interesting time points that can be selected as endpoints in assays without continuous readout. We describe several parameters to characterize the compounds' cytotoxicity and their antiviral activity profile. In addition, the CEI patterns provide valuable additional information about the presumed mechanism of action of these compounds. Finally, as a proof of concept, we used CEI to evaluate the antiviral activity of a small series of compounds, for which we demonstrate that the sulfonated polymer PRO2000 inhibits ZIKV with a response profile representative for a viral entry inhibitor. Overall, we demonstrate for the first time that CEI is a powerful technology to evaluate and characterize compounds against ZIKV replication in a real-time, label-free, and noninvasive manner. Zika virus can cause serious disease in humans. Unfortunately, no antiviral drugs are available to treat infection. Here, we use an impedance-based method to continuously monitor virus infection in-and damage to-human cells. We can determine the Zika viral dose with this technique and also evaluate whether antiviral compounds protect the cells from damage caused by virus replication. We also show that this technique can be used to further unravel the characteristics of these compounds, such as their toxicity to the cells, and that it might even give further insight in their mechanism of antiviral action. Finally, we also find a novel Zika virus inhibitor, PRO2000. Overall, in this study, we use the impedance technology to-for the first time-evaluate compounds with anti-Zika virus properties, and therefore it can add valuable information in the further search for antiviral drugs.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Electric Impedance; Humans; Vero Cells; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 35862960
DOI: 10.1128/spectrum.00491-22 -
Journal of Infection in Developing... Feb 2022Remarkable scientific breakthroughs have been made in the stride towards the development of potent and tolerable hepatitis C regimens within the last three decades.... (Review)
Review
Remarkable scientific breakthroughs have been made in the stride towards the development of potent and tolerable hepatitis C regimens within the last three decades. Earlier approaches involved the use of pegylated interferon alfa and ribavirin as standard-of-care treatment. Treating genotype 1a infection with this regimen which was at that time considered the gold standard for hepatitis C virus therapy was rife with challenges; safety and toxicity issues necessitated a rigorous quest for alternative regimens. Deeper understanding of the pathogenesis of hepatitis C virus ushered in the era of direct acting antiviral agents. These agents have been the subject of intensive research in the last two decades, leading to the development of drug classes such as protease inhibitors (e.g., grazoprevir), NS5A inhibitors (e.g., daclatasvir) and NS5B inhibitors (e.g., sofosbuvir). While many are still under development, several have been approved for hepatitis C therapy. A number of studies investigating the combination of direct acting antiviral agents with or without pegylated interferon and/or ribavirin for the treatment of chronic hepatitis have demonstrated sustained virologic response of > 90%. Given the array of direct acting antiviral agents currently available, the present landscape of hepatitis C therapy is now characterized by a gradual transition to all-oral interferon-free regimens. Despite these milestones, the WHO global target of eliminating hepatitis C as a public health problem by 2030 seems uncertain. In this review, we provide a concise account of the evolution and advancements in the development of anti-HCV regimens.
Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Interferon-alpha
PubMed: 35298416
DOI: 10.3855/jidc.14485 -
International Journal of Molecular... Mar 2023The emergence of the SARS-CoV-2 coronavirus has garnered global attention due to its highly pathogenic nature and the resulting health crisis and economic burden.... (Review)
Review
The emergence of the SARS-CoV-2 coronavirus has garnered global attention due to its highly pathogenic nature and the resulting health crisis and economic burden. Although drugs such as Remdesivir have been considered a potential cure by targeting the virus on its RNA polymerase, the high mutation rate and unique 3' to 5' exonuclease with proofreading function make it challenging to develop effective anti-coronavirus drugs. As a result, there is an increasing focus on host-virus interactions because coronaviruses trigger stress responses, cell cycle changes, apoptosis, autophagy, and the dysregulation of immune function and inflammation in host cells. The p53 tumor suppressor molecule is a critical regulator of cell signaling pathways, cellular stress responses, DNA repair, and apoptosis. However, viruses can activate or inhibit p53 during viral infections to enhance viral replication and spread. Given its pivotal role in cell physiology, p53 represents a potential target for anti-coronavirus drugs. This review aims to summarize the relationship between p53 and coronaviruses from various perspectives, to shed light on potential targets for antiviral drug development and vaccine design.
Topics: Humans; Host Microbial Interactions; Tumor Suppressor Protein p53; COVID-19; SARS-CoV-2; Antiviral Agents; Virus Replication
PubMed: 37047343
DOI: 10.3390/ijms24076371