ABSTRACT
Since 2019, COVID-19 has been raging around the world. Respiratory viral infectious diseases such as influenza and respiratory syncytial virus (RSV) infection are also prevalent, with influenza having the ability to cause seasonal pandemics. While vaccines and antiviral drugs are available to prevent and treat disease, herbal extracts would be another option. This study investigated the inhibitory effects of extracts of Echinacea purpurea (EP) and Ganoderma lucidum (G. lucidum) and the advanced G. lucidum drink (AG) on influenza A/B viruses. To determine whether EP and G. lucidum extracts enhance cell immunity and thus prevent virus infection or act to directly suppress viruses, cell survival and hemagglutination (HA) assays were used in this study. Cells were treated with samples at different concentrations (each sample concentration was tested from the highest non-cytotoxic concentration) and incubated with influenza A/B for 24 h, with the results showing that both G. lucidum and EP extracts and mixtures exhibited the ability to enhance cell survival against viruses. In the HA assay, AG and EP extract showed good inhibitory effect on influenza A/B viruses. All of the samples demonstrated an improvement of the mitochondrial membrane potential and improved resistance to influenza A/B virus infection. EP and G. lucidum extracts at noncytotoxic concentrations increased cell viability, but only AG and EP extract directly decreased influenza virus titers. In conclusion, results indicate the ability of EP and G. lucidum extract to prevent viruses from entering cells by improving cell viability and mitochondrial dysfunction and EP extract showed direct inhibition on viruses and prevented viral infection at post-infection strategy.
Subject(s)
Antiviral Agents , Cell Survival , Echinacea , Influenza A virus , Influenza B virus , Influenza, Human , Plant Extracts , Reishi , Reishi/chemistry , Influenza B virus/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Echinacea/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Humans , Cell Survival/drug effects , Influenza, Human/drug therapy , Influenza, Human/virology , Influenza A virus/drug effects , Animals , Madin Darby Canine Kidney Cells , DogsABSTRACT
Ruzotolimod (Toll-like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno-modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug-related adverse events of flu-like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu-like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC-suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu-like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu-like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN-α, neopterin, IP-10, and the transcriptional expression of ISG15, OAS-1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu-like symptoms occurrence increases with PD responses (IFN-α and IP-10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug-related flu-like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu-like symptoms.
Subject(s)
Healthy Volunteers , Hepatitis B, Chronic , Toll-Like Receptor 7 , Humans , Toll-Like Receptor 7/agonists , Male , Adult , Female , Middle Aged , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/immunology , Hepatitis B, Chronic/virology , Hepatitis B, Chronic/blood , Young Adult , Antiviral Agents/pharmacokinetics , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Influenza, Human/drug therapy , Influenza, Human/immunology , Dose-Response Relationship, Drug , Adolescent , Administration, Oral , Organic ChemicalsABSTRACT
BACKGROUND: The optimal antiviral drug for treatment of severe influenza remains unclear. To support updated WHO influenza clinical guidelines, this systematic review and network meta-analysis evaluated antivirals for treatment of patients with severe influenza. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023, that enrolled hospitalised patients with suspected or laboratory-confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or another antiviral. Pairs of coauthors independently extracted data on study characteristics, patient characteristics, antiviral characteristics, and outcomes, with discrepancies resolved by discussion or by a third coauthor. Key outcomes of interest were time to alleviation of symptoms, duration of hospitalisation, admission to intensive care unit, progression to invasive mechanical ventilation, duration of mechanical ventilation, mortality, hospital discharge destination, emergence of antiviral resistance, adverse events, adverse events related to treatments, and serious adverse events. We conducted frequentist network meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. This study is registered with PROSPERO, CRD42023456650. FINDINGS: Of 11â878 records identified by our search, eight trials with 1424 participants (mean age 36-60 years for trials that reported mean or median age; 43-78% male patients) were included in this systematic review, of which six were included in the network meta-analysis. The effects of oseltamivir, peramivir, or zanamivir on mortality compared with placebo or standard care without placebo for seasonal and zoonotic influenza were of very low certainty. Compared with placebo or standard care, we found low certainty evidence that duration of hospitalisation for seasonal influenza was reduced with oseltamivir (mean difference -1·63 days, 95% CI -2·81 to -0·45) and peramivir (-1·73 days, -3·33 to -0·13). Compared with standard care, there was little or no difference in time to alleviation of symptoms with oseltamivir (0·34 days, -0·86 to 1·54; low certainty evidence) or peramivir (-0·05 days, -0·69 to 0·59; low certainty evidence). There were no differences in adverse events or serious adverse events with oseltamivir, peramivir, and zanamivir (very low certainty evidence). Uncertainty remains about the effects of antivirals on other outcomes for patients with severe influenza. Due to the small number of eligible trials, we could not test for publication bias. INTERPRETATION: In hospitalised patients with severe influenza, oseltamivir and peramivir might reduce duration of hospitalisation compared with standard care or placebo, although the certainty of evidence is low. The effects of all antivirals on mortality and other important patient outcomes are very uncertain due to scarce data from randomised controlled trials. FUNDING: World Health Organization.
Subject(s)
Antiviral Agents , Influenza, Human , Network Meta-Analysis , Randomized Controlled Trials as Topic , Humans , Influenza, Human/drug therapy , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Hospitalization/statistics & numerical data , Oseltamivir/therapeutic use , Oseltamivir/adverse effects , Male , Zanamivir/therapeutic useABSTRACT
Although rapid progression and a poor prognosis in influenza A virus (IAV) infection-induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV-induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV-infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV-inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1-dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV-infected pDHBE cells; however, these changes were rescued by OMA1-siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV-induced cellular energy exhaustion via OMA1-OPA1-S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV.
Subject(s)
Energy Metabolism , GTP Phosphohydrolases , Influenza A virus , Melatonin , Pulmonary Disease, Chronic Obstructive , Humans , Energy Metabolism/drug effects , GTP Phosphohydrolases/metabolism , GTP Phosphohydrolases/genetics , Influenza A virus/drug effects , Influenza, Human/metabolism , Influenza, Human/drug therapy , Melatonin/pharmacology , Metalloendopeptidases , Oxidative Phosphorylation/drug effects , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapyABSTRACT
This study aimed to compare the 2-year cardio-cerebrovascular adverse outcomes of patients with influenza with and without preexisting cardiovascular disease (preCVD) treated with oral antiviral agents in the outpatient clinic. Oral antiviral agents are routinely prescribed to treat influenza infection with a positive rapid-antigen test in the outpatient clinic; however, influenza-associated cardio-cerebrovascular outcomes have not yet been characterized in patients with preCVD treated with oral antiviral agents. Data between 2006 and 2016 were extracted from the National Health Database of South Korea. A total of 865,522 patients with influenza treated with oral antiviral agents were selected in South Korea and classified as preexisting ischemic heart disease (IHD), heart failure (HF), or atrial fibrillation (AF), and 2-year cardio-cerebrovascular outcomes were analyzed using a Cox proportional hazard regression model. Among the participants, 96,433 had preCVD (11.1%; mean age, 46 years) including IHD (86.4%), HF (23.1%), and AF (12.5%). The incidence of new-onset IHD, AF, HF, and death was similar between patients with influenza with and without preCVD. The incidences of IHD and stroke were 0.489 and 0.047 per 100-person year in the preCVD group, respectively. The incidence of cardiovascular mortality was 0.489 per 100-person year in the preCVD group, and the hazard ratio for cardiovascular mortality in the preCVD group was not significantly different from that in patients without preCVD. Based on the national health data, 2-year cardio-cerebrovascular adverse outcomes were not significantly different between patients with and without preCVD treated with oral antiviral agents.
Subject(s)
Antiviral Agents , Cardiovascular Diseases , Influenza, Human , Humans , Influenza, Human/drug therapy , Influenza, Human/complications , Influenza, Human/mortality , Influenza, Human/epidemiology , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Male , Female , Middle Aged , Republic of Korea/epidemiology , Cardiovascular Diseases/epidemiology , Adult , Administration, Oral , Aged , Incidence , Myocardial Ischemia/epidemiology , Myocardial Ischemia/drug therapy , Heart Failure/drug therapy , Heart Failure/epidemiology , Retrospective Studies , Atrial Fibrillation/drug therapy , Atrial Fibrillation/epidemiology , Atrial Fibrillation/complications , Proportional Hazards ModelsABSTRACT
Background: Adverse effects of proton pump inhibitors (PPIs) have raised wide concerns. The association of PPIs with influenza is unexplored, while that with pneumonia or COVID-19 remains controversial. Our study aims to evaluate whether PPI use increases the risks of these respiratory infections. Methods: The current study included 160,923 eligible participants at baseline who completed questionnaires on medication use, which included PPI or histamine-2 receptor antagonist (H2RA), from the UK Biobank. Cox proportional hazards regression and propensity score-matching analyses were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Comparisons with H2RA users were tested. PPI use was associated with increased risks of developing influenza (HR 1.32, 95% CI 1.12-1.56) and pneumonia (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.26-1.59). In contrast, the risk of COVID-19 infection was not significant with regular PPI use (HR 1.08, 95% CI 0.99-1.17), while the risks of severe COVID-19 (HR 1.19. 95% CI 1.11-1.27) and mortality (HR 1.37. 95% CI 1.29-1.46) were increased. However, when compared with H2RA users, PPI users were associated with a higher risk of influenza (HR 1.74, 95% CI 1.19-2.54), but the risks with pneumonia or COVID-19-related outcomes were not evident. Conclusions: PPI users are associated with increased risks of influenza, pneumonia, as well as COVID-19 severity and mortality compared to non-users, while the effects on pneumonia or COVID-19-related outcomes under PPI use were attenuated when compared to the use of H2RAs. Appropriate use of PPIs based on comprehensive evaluation is required. Funding: This work is supported by the National Natural Science Foundation of China (82171698, 82170561, 81300279, 81741067, 82100238), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), the Guangdong Basic and Applied Basic Research Foundation (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJH201923, DFJH201803, KJ012019099, KJ012021143, KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL).
Subject(s)
COVID-19 , Influenza, Human , Pneumonia , Proton Pump Inhibitors , Humans , Proton Pump Inhibitors/adverse effects , Influenza, Human/drug therapy , Male , Female , COVID-19/epidemiology , Middle Aged , Aged , Cohort Studies , Pneumonia/epidemiology , Histamine H2 Antagonists/adverse effects , Histamine H2 Antagonists/therapeutic use , SARS-CoV-2 , Adult , United Kingdom/epidemiology , Disease Susceptibility , Proportional Hazards ModelsABSTRACT
Influenza (Flu) is a severe health, medical, and economic problem, but no medication that has excellent outcomes and lowers the occurrence of these problems is now available. GanghuoQingwenGranules (GHQWG) is a common Chinese herbal formula for the treatment of influenza (flu). However, its methods of action remain unknown. We used network pharmacology, molecular docking, and molecular dynamics simulation techniques to investigate the pharmacological mechanism of GHQWG in flu. TCMSP and various types of literature were used to obtain active molecules and targets of GHQWG. Flu-related targets were found in the Online Mendelian Inheritance in Man (OMIM) database, the DisFeNET database, the Therapeutic Target Database (TTD), and the DrugBank database. To screen the key targets, a protein-protein interaction (PPI) network was constructed. DAVID was used to analyze GO and KEGG pathway enrichment. Target tissue and organ distribution was assessed. Molecular docking was used to evaluate interactions between possible targets and active molecules. For the ideal core protein-compound complexes obtained using molecular docking, a molecular dynamics simulation was performed. In total, 90 active molecules and 312 GHQWG targets were discovered. The PPI network's topology highlighted six key targets. GHQWG's effects are mediated via genes involved in inflammation, apoptosis, and oxidative stress, as well as the TNF and IL-17 signaling pathways, according to GO and KEGG pathway enrichment analysis. Molecular docking and molecular dynamics simulations demonstrated that the active compounds and tested targets had strong binding capabilities. This analysis accurately predicts the effective components, possible targets, and pathways involved in GHQWG flu treatment. We proposed a novel study strategy for future studies on the molecular processes of GHQWG in flu treatment. Furthermore, the possible active components provide a dependable source for flu drug screening.
Subject(s)
Drugs, Chinese Herbal , Influenza, Human , Molecular Docking Simulation , Molecular Dynamics Simulation , Network Pharmacology , Protein Interaction Maps , Humans , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/virology , Protein Interaction Maps/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/therapeutic useABSTRACT
Selaginella tamariscina is a perennial plant that is used for diverse diseases. This study investigated whether Selaginella tamariscina has an antiviral effect against influenza A virus (IAV) infection. We used green fluorescent protein (GFP)-tagged influenza A virus (IAV) to examine the effect of Selaginella tamariscina ethanol extract (STE) on influenza viral infection. Fluorescence microscopy and flow cytometry showed that STE potently represses GFP expression by the virus, dose-dependently. STE significantly inhibited the expression of the IAV M2, NP, HA, NA, NS1, and PB2 proteins. Time-of-addition and hemagglutination inhibition assays showed that STE has an inhibitory effect on hemagglutinin and viral binding on the cells at an early infection time. In addition, STE exerted a suppressive effect on the neuraminidase activity of the H1N1 and H3N2 IAVs. Furthermore, dose-dependently, STE inhibited the cytopathic effect induced by H3N2, as well as by H1N1 IAV. Especially in the presence of 200 µg/mL STE, the cytopathic effect was completely blocked. Our findings suggest that STE has antiviral efficacy against IAV infection; thus, it could be developed as a natural IAV inhibitor.
Subject(s)
Antiviral Agents , Ethanol , Influenza A Virus, H1N1 Subtype , Influenza A Virus, H3N2 Subtype , Neuraminidase , Plant Extracts , Selaginellaceae , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Plant Extracts/pharmacology , Antiviral Agents/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Humans , Influenza A Virus, H3N2 Subtype/drug effects , Animals , Madin Darby Canine Kidney Cells , Selaginellaceae/chemistry , Dogs , Influenza A virus/drug effects , Hemagglutinins/metabolism , Influenza, Human/drug therapyABSTRACT
Tagetes erecta Linn. (TE) is traditionally used to treat cardiovascular, renal, and gastrointestinal diseases. In this study, we investigated the active compounds and targets of TE extract that may exert antiviral effects against influenza A. Active compounds and targets of TE extract were identified using the Traditional Chinese Medicine Systems Pharmacology database (TCSMP). The influenza A-related gene set was screened using GeneCards and the Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction (PPI) network was built to establish the hub targets. Pathway and target studies were conducted using Gene Expression Omnibus (GEO). The interactions between active compounds and potential targets were assessed by molecular docking. An in vitro study was performed using antiviral and plaque reduction assays. From the compound and target search, we identified 6 active compounds and 95 potential targets. We retrieved 887 influenza-associated target genes and determined 14 intersecting core targets between TE and influenza. After constructing a compound-target network, we discovered lutein and beta-carotene to be the key compounds. Next, PPI network analysis identified the top three hub genes associated with influenza (IL-6, HIF1A, and IL-1ß). Similarly, GEO analysis revealed IL-6, TGFB1, and CXCL8 to be the top three target genes. In our docking study, we identified that lutein and IL-6 had the strongest bindings. Our in vitro experimental results revealed that the TE extract exhibited therapeutic rather than prophylactic effects on influenza disease. We identified lutein as a main active compound in TE extract, and IL-6 as an important target associated with influenza, by using data mining and bioinformatics. Our in vitro findings indicated that TE extract exerted protective properties against the influenza A virus. We speculated that lutein, as a key active component in TE extract, is largely responsible for its antiviral effects. Therefore, we suggest TE extract as an alternative in the treatment of influenza.
Subject(s)
Antiviral Agents , Computational Biology , Molecular Docking Simulation , Plant Extracts , Protein Interaction Maps , Tagetes , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Computational Biology/methods , Protein Interaction Maps/drug effects , Humans , Tagetes/chemistry , Influenza A virus/drug effects , Influenza A virus/genetics , Influenza, Human/drug therapy , Influenza, Human/virology , Animals , Madin Darby Canine Kidney Cells , Dogs , Medicine, Chinese Traditional/methodsABSTRACT
Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.
Subject(s)
Amino Acid Substitution , Antiviral Agents , Dibenzothiepins , Drug Resistance, Viral , Influenza A Virus, H3N2 Subtype , Influenza, Human , Morpholines , Pyridones , Triazines , Viral Proteins , Humans , Dibenzothiepins/therapeutic use , Dibenzothiepins/pharmacology , Influenza, Human/drug therapy , Influenza, Human/virology , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/enzymology , Triazines/therapeutic use , Triazines/pharmacology , Japan , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Morpholines/therapeutic use , Drug Resistance, Viral/genetics , Child , Adult , Child, Preschool , Adolescent , Viral Proteins/genetics , RNA-Dependent RNA Polymerase/genetics , Female , Male , Thiepins/therapeutic use , Thiepins/pharmacology , Infant , Middle Aged , Seasons , Pyridines/therapeutic use , Pyridines/pharmacology , Young Adult , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/drug effects , AgedABSTRACT
Background: Influenza A (H1N1) virus is a highly contagious respiratory disease that causes severe illness and death. Vaccines and antiviral drugs are limited by viral variation and drug resistance, so developing efficient integrated theranostic options appears significant in anti-influenza virus infection. Methods: In this study, we designed and fabricated covalent organic framework (COF) based theranostic platforms (T705@DATA-COF-Pro), which was composed of an RNA polymerase inhibitor (favipiravir, T705), the carboxyl-enriched COF (DATA-COF) nano-carrier and Cy3-labeled single DNA (ssDNA) probe. Results: The multi-porosity COF core provided an excellent micro-environment and smooth delivery for T705. The ssDNA probe coating bound to the nucleic acids of H1N1 selectively, thus controlling drug release and allowing fluorescence imaging. The combination of COF and probe triggered the synergism, promoting drug further therapeutic outcomes. With the aid of T705@DATA-COF-Pro platforms, the H1N1-infected mouse models lightly achieved diagnosis and significantly prolonged survival. Conclusion: This research underscores the distinctive benefits and immense potential of COF materials in nano-preparations for virus infection, offering novel avenues for the detection and treatment of H1N1 virus infection.
Subject(s)
Antiviral Agents , Influenza A Virus, H1N1 Subtype , Metal-Organic Frameworks , Orthomyxoviridae Infections , Theranostic Nanomedicine , Influenza A Virus, H1N1 Subtype/drug effects , Animals , Theranostic Nanomedicine/methods , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Mice , Orthomyxoviridae Infections/drug therapy , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Humans , Amides/chemistry , Amides/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Influenza, Human/drug therapy , Mice, Inbred BALB C , Madin Darby Canine Kidney Cells , Drug Carriers/chemistry , Dogs , Drug LiberationABSTRACT
Baloxavir acid (BXA) is a pan-influenza antiviral that targets the cap-dependent endonuclease of the polymerase acidic (PA) protein required for viral mRNA synthesis. To gain a comprehensive understanding on the molecular changes associated with reduced susceptibility to BXA and their fitness profile, we performed a deep mutational scanning at the PA endonuclease domain of an A (H1N1)pdm09 virus. The recombinant virus libraries were serially passaged in vitro under increasing concentrations of BXA followed by next-generation sequencing to monitor PA amino acid substitutions with increased detection frequencies. Enriched PA amino acid changes were each introduced into a recombinant A (H1N1)pdm09 virus to validate their effect on BXA susceptibility and viral replication fitness in vitro. The I38 T/M substitutions known to confer reduced susceptibility to BXA were invariably detected from recombinant virus libraries within 5 serial passages. In addition, we identified a novel L106R substitution that emerged in the third passage and conferred greater than 10-fold reduced susceptibility to BXA. PA-L106 is highly conserved among seasonal influenza A and B viruses. Compared to the wild-type virus, the L106R substitution resulted in reduced polymerase activity and a minor reduction of the peak viral load, suggesting the amino acid change may result in moderate fitness loss. Our results support the use of deep mutational scanning as a practical tool to elucidate genotype-phenotype relationships, including mapping amino acid substitutions with reduced susceptibility to antivirals.
Subject(s)
Amino Acid Substitution , Antiviral Agents , Dibenzothiepins , Drug Resistance, Viral , Influenza A Virus, H1N1 Subtype , Morpholines , Pyridones , Triazines , Viral Proteins , Virus Replication , Dibenzothiepins/pharmacology , Drug Resistance, Viral/genetics , Antiviral Agents/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H1N1 Subtype/genetics , Triazines/pharmacology , Virus Replication/drug effects , Pyridones/pharmacology , Humans , Morpholines/pharmacology , Viral Proteins/genetics , Animals , Thiepins/pharmacology , RNA-Dependent RNA Polymerase/genetics , High-Throughput Nucleotide Sequencing , Dogs , Madin Darby Canine Kidney Cells , Influenza, Human/virology , Influenza, Human/drug therapy , Oxazines/pharmacologyABSTRACT
Influenza remains a global public health threat, and the development of new antivirals is crucial to combat emerging drug-resistant influenza strains. In this study, we report the synthesis and evaluation of a sialyl lactosyl (TS)-bovine serum albumin (BSA) conjugate as a potential multivalent inhibitor of the influenza virus. The key trisaccharide component, TS, was efficiently prepared via a chemoenzymatic approach, followed by conjugation to dibenzocyclooctyne-modified BSA via a strain-promoted azide-alkyne cycloaddition reaction. Biophysical and biochemical assays, including surface plasmon resonance, isothermal titration calorimetry, hemagglutination inhibition, and neuraminidase inhibition, demonstrated the strong binding affinity of TS-BSA to the hemagglutinin (HA) and neuraminidase (NA) proteins of the influenza virus as well as intact virion particles. Notably, TS-BSA exhibited potent inhibitory activity against viral entry and release, preventing cytopathic effects in cell culture. This multivalent presentation strategy highlights the potential of glycocluster-based antivirals for combating influenza and other drug-resistant viral strains.
Subject(s)
Antiviral Agents , Serum Albumin, Bovine , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/metabolism , Animals , Humans , Influenza, Human/drug therapy , Structure-Activity Relationship , Dose-Response Relationship, Drug , Molecular Structure , Dogs , Cattle , Microbial Sensitivity Tests , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Virus Internalization/drug effects , Madin Darby Canine Kidney Cells/drug effects , Influenza A Virus, H1N1 Subtype/drug effects , GlycosidesABSTRACT
INTRODUCTION: Since the coronavirus disease 2019-mandated social distancing policy has been lifted worldwide, the circulation of influenza is expected to resume. Currently, oseltamivir is approved as the first-line agent for influenza prevention and treatment. AREAS COVERED: This paper reviews the updated evidence in the pharmacology, resistance mechanisms, clinical pharmacy management, and real-world data on oseltamivir for influenza. EXPERT OPINION: Oseltamivir is an oral prodrug of oseltamivir carboxylate, an influenza A and B neuraminidase inhibitor. Recently, the therapeutic efficacy of oseltamivir has been demonstrated in several trials. Oseltamivir is generally well-tolerated but may lead to neuropsychiatric events and bleeding. Oseltamivir-resistant influenza virus has been associated with the H275Y mutation in the influenza A(H1N1)pdm09 virus, while most strains are still sensitive to oseltamivir. Dose adjustment for oseltamivir should be based on creatinine clearance and body weight in pediatric patients with renal failure. According to real-world data from Nanfang Hospital, the annual number of patients prescribed oseltamivir declined from 35,711 in 2019 to 8,971 in 2020, with marked increases in 2022 (20,213) and 2023 (18,071). Among the 206 inpatients, children aged < 6 years who were treated with oseltamivir had the shortest duration to defervescence.
Subject(s)
Antiviral Agents , Drug Resistance, Viral , Influenza, Human , Oseltamivir , Oseltamivir/therapeutic use , Humans , Antiviral Agents/therapeutic use , Influenza, Human/drug therapy , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H1N1 Subtype/geneticsABSTRACT
Since May 2023, a novel combination of neuraminidase mutations, I223V + S247N, has been detected in influenza A(H1N1)pdm09 viruses collected in countries spanning 5 continents, mostly in Europe (67/101). The viruses belong to 2 phylogenetically distinct groups and display ≈13-fold reduced inhibition by oseltamivir while retaining normal susceptibility to other antiviral drugs.
Subject(s)
Antiviral Agents , Drug Resistance, Viral , Influenza A Virus, H1N1 Subtype , Influenza, Human , Neuraminidase , Oseltamivir , Phylogeny , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H1N1 Subtype/genetics , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Influenza, Human/virology , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Neuraminidase/antagonists & inhibitors , Neuraminidase/genetics , Drug Resistance, Viral/genetics , MutationABSTRACT
INTRODUCTION: Influenza affects individuals of all ages and poses a significant threat during pandemics, epidemics, and sporadic outbreaks. Neuraminidase inhibitors (NAIs) are currently the first choice in the treatment and prevention of influenza, but their use can be hindered by viral resistance. AREAS COVERED: This review summarizes current NAIs pharmacological profiles, their current place in therapy, and the mechanisms of viral resistance and outlines possible new indications, ways of administration, and novel candidate NAIs compounds. EXPERT OPINION: NAIs represent a versatile group of compounds with diverse administration methods and pharmacokinetics. While the prevalence of influenza virus resistance to NAIs remains low, there is heightened vigilance due to the pandemic potential of influenza. Several novel NAIs and derivatives are currently under assessment at various stages of development for the treatment and prevention of influenza.
Subject(s)
Antiviral Agents , Drug Resistance, Viral , Enzyme Inhibitors , Influenza, Human , Neuraminidase , Humans , Neuraminidase/antagonists & inhibitors , Influenza, Human/drug therapy , Antiviral Agents/therapeutic use , Antiviral Agents/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/pharmacology , Drug Development , AnimalsABSTRACT
Importance: Severe pulmonary infections, including COVID-19, community-acquired pneumonia, influenza, and Pneumocystis pneumonia, are a leading cause of death among adults worldwide. Pulmonary infections in critically ill patients may cause septic shock, acute respiratory distress syndrome, or both, which are associated with mortality rates ranging between 30% and 50%. Observations: Corticosteroids mitigate the immune response to infection and improve outcomes for patients with several types of severe pulmonary infections. Low-dose corticosteroids, defined as less than or equal to 400 mg hydrocortisone equivalent daily, can reduce mortality of patients with severe COVID-19, community-acquired pneumonia, and Pneumocystis pneumonia. A randomized clinical trial of 6425 patients hospitalized with COVID-19 who required supplemental oxygen or noninvasive or invasive mechanical ventilation reported that dexamethasone 6 mg daily for 10 days decreased 28-day mortality (23% vs 26%). A meta-analysis that included 7 randomized clinical trials of 1689 patients treated in the intensive care unit for severe bacterial community-acquired pneumonia reported that hydrocortisone equivalent less than or equal to 400 mg daily for 8 days or fewer was associated with lower 30-day mortality compared with placebo (10% vs 16%). In a meta-analysis of 6 randomized clinical trials, low-dose corticosteroids were associated with lower mortality rates compared with placebo for patients with HIV and moderate to severe Pneumocystis pneumonia (13% vs 25%). In a predefined subgroup analysis of a trial of low-dose steroid treatment for septic shock, patients with community-acquired pneumonia randomized to 7 days of intravenous hydrocortisone 50 mg every 6 hours and fludrocortisone 50 µg daily had decreased mortality compared with the placebo group (39% vs 51%). For patients with acute respiratory distress syndrome caused by various conditions, low-dose corticosteroids were associated with decreased in-hospital mortality (34% vs 45%) according to a meta-analysis of 8 studies that included 1091 patients. Adverse effects of low-dose corticosteroids may include hyperglycemia, gastrointestinal bleeding, neuropsychiatric disorders, muscle weakness, hypernatremia, and secondary infections. Conclusions and Relevance: Treatment with low-dose corticosteroids is associated with decreased mortality for patients with severe COVID-19 infection, severe community-acquired bacterial pneumonia, and moderate to severe Pneumocystis pneumonia (for patients with HIV). Low-dose corticosteroids may also benefit critically ill patients with respiratory infections who have septic shock, acute respiratory distress syndrome, or both.
Subject(s)
Community-Acquired Infections , Critical Illness , Pneumonia, Pneumocystis , Humans , Community-Acquired Infections/drug therapy , Pneumonia, Pneumocystis/drug therapy , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/therapeutic use , Adult , Hydrocortisone/therapeutic use , Hydrocortisone/administration & dosage , COVID-19 Drug Treatment , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Dexamethasone/adverse effects , Pneumonia, Viral/drug therapy , Pneumonia, Viral/mortality , Influenza, Human/drug therapy , Influenza, Human/mortality , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/mortalityABSTRACT
Influenza A virus (IAV) continuously poses a considerable threat to global health through seasonal epidemics and recurring pandemics. IAV RNA-dependent RNA polymerases (FluPol) mediate the transcription of RNA and replication of the viral genome. Searching for targets that inhibit viral polymerase activity helps us develop better antiviral drugs. Here, we identified heterogeneous nuclear ribonucleoprotein A/B (hnRNPAB) as an anti-influenza host factor. hnRNPAB interacts with NP of IAV to inhibit the interaction between PB1 and NP, which is dependent on the 5-amino-acid peptide of the hnRNPAB C-terminal domain (aa 318-322). We further found that the 5-amino-acid peptide blocks the interaction between PB1 and NP to destroy the FluPol activity. In vivo studies demonstrate that hnRNPAB-deficient mice display higher viral burdens, enhanced cytokine production, and increased mortality after influenza infection. These data demonstrate that hnRNPAB perturbs FluPol complex conformation to inhibit IAV infection, providing insights into anti-influenza defense mechanisms.
Subject(s)
Influenza A virus , Orthomyxoviridae Infections , RNA-Dependent RNA Polymerase , Virus Replication , Animals , Dogs , Humans , Mice , A549 Cells , Antiviral Agents/pharmacology , HEK293 Cells , Influenza A virus/drug effects , Influenza, Human/virology , Influenza, Human/drug therapy , Madin Darby Canine Kidney Cells , Mice, Inbred C57BL , Mice, Knockout , Nucleocapsid Proteins , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/virology , RNA-Dependent RNA Polymerase/metabolism , RNA-Dependent RNA Polymerase/genetics , Viral Proteins/metabolism , Viral Proteins/genetics , Virus Replication/drug effectsABSTRACT
Human interferon α2 (IFNα2) is a cytokine with broad-spectrum antiviral activity, and its engineered forms are widely used to treat viral infections. However, IFNα2 may trigger proinflammatory responses and underlying side effects during treatment. Trefoil factor 2 (TFF2) is a secreted protein with anti-inflammatory properties. Here, we explored whether coupling IFNα2 to TFF2 in a two-in-one fusion form could combine the beneficial effects of both molecules on viral infections toward a more desirable treatment outcome. We engineered two forms of human IFNα2 and TFF2 fusion proteins, IFNα2-TFF2-Fc (ITF) and TFF2-IFNα2-Fc (TIF), and examined their properties in vitro in comparison to IFNα2 and TFF2 alone. RNA-Seq was further used to explore such comparison on dynamic gene regulation at transriptomic level. These in vitro assessments collectively indicated that TIF largely retained the antiviral activity of IFNα2 while being a weaker inflammation inducer, consistent with the presence of TFF2 activity. We further demonstrated the superiority of TIF over IFNα2 or TFF2 alone in treating influenza infection using a mouse infection model. Together, our study provided evidence supporting that, by possessing antiviral activity conferred by IFNα2 with complementation from TFF2 in suppressing the inflammatory side effects, the fusion proteins, particularly TIF, represent more effective agents against influenza and other respiratory viral infections than IFNα2 or TFF2 alone. It implies that merging two molecules with complementary functions holds potential for developing novel therapeutics against viral infections.