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During in silico research, based on molecular docking, dynamics simulation, network pharmacology and ADMET (absorption, distribution, metabolism, excretion, and toxicity) property, 31 potential compounds are obtained from seven Chinese medicinal herbs containing coumarins. Moreover, mechanism researches discover these compounds treat influenza A virus through key targets TLR4, MMP9, and IL6 (high fever, acute respiratory distress syndrome), MAPK1 and MAPK3 (MAPK signaling pathway, viral RNP export and viral protein expression), CASP3 (apoptosis), EP300 and CREBBP (viral myocarditis, chemoattraction of monocytes and macrophages, T cell activation antibody response). Further experimental verification finds that 22 of 31 compounds have various degrees of anti‐influenza virus activities. Moreover, 12 of 22 compounds have better biological activities (IC50=0.1609–54.95 μM) than oseltamivir (IC50=114.3 μM). 3 of 12 compounds have better antioxidant activities (IC50=2.087–3.796 μM) than vitamin C (IC50=5.004 μM). Therefore, ellagic acid, hyperoside, and fraxetin are promising multi‐target lead compounds for influenza virus therapy. Meanwhile, the present study offers compelling evidence for the development of novel antiviral medications. [ABSTRACT FROM AUTHOR]

Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza. [ABSTRACT FROM AUTHOR]

Background Pandemic influenza virus is a public health issue, and the neuraminidase inhibitors (NIs) “Oseltamivir” and “Zanamivir” are effective treatments. While teenagers use NIs, there are concerns regarding neuropsychiatric adverse events (NPAEs). Aim We aimed to use the Taiwan National Health Insurance Research Database to identify the correlation between NPAEs and NIs use in teenagers aged 13–19 years. Methods The final population between 2000 and 2015 included in this study was 3698 individuals, with 2287 individuals having received “Oseltamivir” and “Zanamivir” (study cohort group) and 9148 individuals not receiving “Oseltamivir” and “Zanamivir” (comparison cohort group). We initially used a multivariate Cox regression analysis during the tracking period to determine the cumulative incidence of NPAEs. Results Our findings revealed no significant increase in the likelihood of developing NPAEs in the study group. The Kaplan–Meier survival curve demonstrated that individuals who received “Oseltamivir” and “Zanamivir” were not associated with statistically significantly increased NPAEs compared with controls (log-rank test, P = 0.724). Conclusion No more risk in comparison of the normal population in our study, and the safety of “Oseltamivir” and “Zanamivir” is established treatments for influenza.

Influenza A virus infection, commonly known as the flu, has persisted in the community for centuries. Although we have yearly vaccinations to prevent seasonal flu, there remains a dire need for antiviral drugs to treat active infections. The constantly evolving genome of the influenza A virus limits the number of effective antiviral therapeutic options. Over time, antiviral drugs become inefficient due to the development of resistance, as seen with adamantanes, which are now largely ineffective against most circulating strains of the virus. Neuraminidase inhibitors have long been the drug of choice, but due to selection pressure, strains are becoming resistant to this class of drugs. Baloxavir marboxil, a drug with a novel mode of action, can be used against strains resistant to other classes of drugs but is still not available in many countries. Deep research into nanoparticles has shown they are effective as antiviral drugs, opening a new avenue of research to use them as antiviral agents with novel modes of action. As this deadly virus, which has killed millions of people in the past, continues to develop resistance, there is an urgent need for new therapeutic agents with novel modes of action to halt active infections in patients. This review article covers the available therapeutic antiviral drug options with different modes of action, their effectiveness, and resistance to various strains of influenza A virus. [ABSTRACT FROM AUTHOR]

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.

In this study, we describe the genetic characteristics of influenza A(H1N1)pdm09 strains detected in Myanmar from 2015 to 2019. Whole genomes from 60 A(H1N1)pdm09 virus isolates were amplified using real-time polymerase chain reaction and successfully sequenced using the Illumina iSeq100 platforms. Eight individual phylogenetic trees were retrieved for each segment along with those of the World Health Organization (WHO)-recommended Southern Hemisphere vaccine strains for the respective years. A(H1N1)pdm09 viruses from 2015 were found to belong to clade 6B, those from 2016 to 6B.1, 2017 to 6B.1A, and 2019 to 6B.1A.5a, and were genetically distinct from the Southern Hemisphere vaccine strains for the respective seasons, A/California/7/2009 and A/Michigan/45/2015. We observed one virus with intra-subtype reassortment, collected in the 2015 season. Importantly, three viruses possessed the H275Y substitution in the neuraminidase protein, appearing to be community-acquired without the prior administration of neuraminidase inhibitors. These viruses exhibited highly reduced susceptibility to oseltamivir and peramivir. This study demonstrates the importance of monitoring genetic variations in influenza viruses that will contribute to the selection of global influenza vaccines. [ABSTRACT FROM AUTHOR]

Various substituted D-hexopypyranosides units with nitrogen-containing functionalities are present in many important natural compounds and pharmaceutical substances. Since their complex structural diversity contributes to a broad spectrum of biological functions and activities, these derivatives are frequently studied. This review covers syntheses of D-hexopyranosides with vicinal nitrogen-containing functionalities since the 1960s, when the first articles emerged. The syntheses are arranged according to the positions of substitutions, to form a relative configuration of vicinal functionalities, and synthetic methodologies. [ABSTRACT FROM AUTHOR]

The antiviral susceptibility of currently circulating (2022–2023) highly pathogenic avian influenza (HPAI) A(H5N1) viruses was assessed by genotypic and phenotypic approaches. The frequency was low for neuraminidase (NA) and polymerase acidic (PA) substitutions associated with reduced inhibition by NA inhibitors (21/2698, 0.78%) or the PA inhibitor baloxavir (14/2600, 0.54%). Phenotypic testing of 22 clade 2.3.2.1a and 2.3.4.4b viruses revealed broad susceptibility to NA inhibitors and baloxavir for a conclusion that most contemporary HPAI A(H5N1) viruses retain susceptibility to antiviral drugs. Novel NA-K432E and NA-T438I substitutions (N2 numbering) were identified at elevated frequencies (104/2698, 3.85%) and caused reduced zanamivir and peramivir inhibition. [ABSTRACT FROM AUTHOR]

Influenza poses a significant threat to public health worldwide, particularly among vulnerable populations such as children, the elderly, immunocompromised individuals, and those with chronic diseases. It is associated with high mortality and morbidity rates. Neuraminidase inhibitors play a crucial role in influenza treatment by mitigating the risk of complications and death. However, the genetic variability of the influenza virus enables the emergence of drug-resistant mutations. This review focuses on the search for new compounds that are not analogous to sialic acid, aiming to inhibit the activity of viral neuraminidase in vitro, viral replication in cell cultures, or animal models. Influenza virus strains that have been reported in the literature present specific mutations that generate resistance to neuraminidase inhibitors. Since these inhibitors bear structural resemblance to sialic acid, the predominant location for these mutations is the enzyme's active site. Consequently, exploring alternative compound classes becomes imperative to circumvent this interaction pattern. These compounds will introduce diverse molecular frameworks, serving as foundational structures for further development through rational drug design, thereby engendering novel antiviral agents targeting influenza. The potential prospects for developing novel influenza antivirals based on these findings are discussed. [ABSTRACT FROM AUTHOR]

Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.

Influenza virus continually challenges both human and animal health. Moreover, influenza viruses are easy to mutate. In a certain degree, vaccines may not catch up with rapid mutant paces of viruses. Anti‐influenza drugs NIs (neuraminidase inhibitors) are one of the best choices. Therefore, based on ADMET properties, eight optimal natural multi‐targets NIs glycosides compounds (IC50 = 0.094–97.275 μM) are found from radix glycyrrhizae, flos sophorae, caulis spatholobi, radix astragali, radix glycyrrhizae, semen astragali complanati, and common fenugreek seed through network pharmacology, molecular docking, dynamics simulation, quantum chemistry, and in vitro experiment. Moreover, mechanism research illustrates these natural compounds treat influenza A virus through key targets TLR4, TNF, and IL6 (high fever, acute respiratory distress syndrome), MAPK1, and MAPK3 (MAPK signaling pathway, viral RNP export, and viral protein expression), IL1B (NOD‐like receptor signaling pathway, suppressed maturation of pro‐IL‐1β and pro‐IL‐18), CASP3 (apoptosis), AKT1 (inhibited premature apoptosis), and EP300 (viral myocarditis, chemoattraction of monocytes and macrophages, T‐cell activation antibody response). [ABSTRACT FROM AUTHOR]

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop. [ABSTRACT FROM AUTHOR]

In this study, we describe the genetic characteristics of influenza A(H1N1)pdm09 strains detected in Myanmar from 2015 to 2019. Whole genomes from 60 A(H1N1)pdm09 virus isolates were amplified using real-time polymerase chain reaction and successfully sequenced using the Illumina iSeq100 platforms. Eight individual phylogenetic trees were retrieved for each segment along with those of the World Health Organization (WHO)-recommended Southern Hemisphere vaccine strains for the respective years. A(H1N1)pdm09 viruses from 2015 were found to belong to clade 6B, those from 2016 to 6B.1, 2017 to 6B.1A, and 2019 to 6B.1A.5a, and were genetically distinct from the Southern Hemisphere vaccine strains for the respective seasons, A/California/7/2009 and A/Michigan/45/2015. We observed one virus with intra-subtype reassortment, collected in the 2015 season. Importantly, three viruses possessed the H275Y substitution in the neuraminidase protein, appearing to be community-acquired without the prior administration of neuraminidase inhibitors. These viruses exhibited highly reduced susceptibility to oseltamivir and peramivir. This study demonstrates the importance of monitoring genetic variations in influenza viruses that will contribute to the selection of global influenza vaccines.

Various substituted D-hexopypyranosides units with nitrogen-containing functionalities are present in many important natural compounds and pharmaceutical substances. Since their complex structural diversity contributes to a broad spectrum of biological functions and activities, these derivatives are frequently studied. This review covers syntheses of D-hexopyranosides with vicinal nitrogen-containing functionalities since the 1960s, when the first articles emerged. The syntheses are arranged according to the positions of substitutions, to form a relative configuration of vicinal functionalities, and synthetic methodologies.

Influenza poses a significant threat to public health worldwide, particularly among vulnerable populations such as children, the elderly, immunocompromised individuals, and those with chronic diseases. It is associated with high mortality and morbidity rates. Neuraminidase inhibitors play a crucial role in influenza treatment by mitigating the risk of complications and death. However, the genetic variability of the influenza virus enables the emergence of drug-resistant mutations. This review focuses on the search for new compounds that are not analogous to sialic acid, aiming to inhibit the activity of viral neuraminidase in vitro, viral replication in cell cultures, or animal models. Influenza virus strains that have been reported in the literature present specific mutations that generate resistance to neuraminidase inhibitors. Since these inhibitors bear structural resemblance to sialic acid, the predominant location for these mutations is the enzyme’s active site. Consequently, exploring alternative compound classes becomes imperative to circumvent this interaction pattern. These compounds will introduce diverse molecular frameworks, serving as foundational structures for further development through rational drug design, thereby engendering novel antiviral agents targeting influenza. The potential prospects for developing novel influenza antivirals based on these findings are discussed.

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected cell to host cells. As such, neuraminidase has emerged as a pivotal target for mitigating influenza and its associated complications. Here, we apply a de novo hybridization approach based on a breed-centric methodology to elucidate novel neuraminidase inhibitors. The breed technique amalgamates established ligand frameworks with the shared target, neuraminidase, resulting in innovative inhibitor constructs. Molecular docking analysis revealed that the seven synthesized breed molecules (designated Breeds 1–7) formed more robust complexes with the neuraminidase receptor than conventional clinical neuraminidase inhibitors such as zanamivir, oseltamivir, and peramivir. Pharmacokinetic evaluations of the seven breed molecules (Breeds 1–7) demonstrated favorable bioavailability and optimal permeability, all falling within the specified parameters for human application. Molecular dynamics simulations spanning 100 nanoseconds corroborated the stability of these breed molecules within the active site of neuraminidase, shedding light on their structural dynamics. Binding energy assessments, which were conducted through MM-PBSA analysis, substantiated the enduring complexes formed by the seven types of molecules and the neuraminidase receptor. Last, the investigation employed a reaction-based enumeration technique to ascertain the synthetic pathways for the synthesis of the seven breed molecules. [ABSTRACT FROM AUTHOR]

The purpose of the present work was to evaluate population immunity to influenza and molecular genetic analysis of influenza viruses detected in the Russian Federation over 2020-2022. In this study, 1344 samples of blood serum collected prior to the 2021-2022 flu season in Siberian, Southern, Far Eastern, Volga and Ural Federal Districts were studied. Seropositivity to the A/Victoria/2570/2019 vaccine strain (H1N1) pdm09 was detected in 25% to 31% of samples from the four federal districts, and in 8% of samples from the Far Eastern Federal District. Seropositivity to the A/Cambodia/e0826360/2020 strain (H3N2) was detected in 24% to 37% of the samples. The lowest population immunity was revealed to the influenza B/Washington/02/2019 vaccine strain (Victoria lineage), with < 10% of serum samples reactive to the studied strain. Since March 2020, the worldwide turnover of all seasonal respiratory viruses has sharply decreased, except of rhinoviruses. From March 2020 to June 2021, we have identified six B/Victoria influenza viruses from sporadic cases of influenza. From June 2021 to the end February 2022, the State Research Center “Vector” received 901 samples positive for influenza A(H3N2) virus RNA, two specimens positive for A(H1N1) pdm09 virus RNA, and 17 samples positive for influenza B. All studied A(H3N2) viruses belonged to the 3C.2a1b.2a2 subclade (Bangladesh group). The two verified A(H1N1) pdm09 influenza viruses belonged to the 6B.1A.5a clade. All studied influenza B viruses were assigned to the B/Victoria genetic lineage, and to 1A.3a2 subclade. The genomes of all identified viruses did not contain mutations of the NA gene responsible for drug resistance to neuraminidase inhibitors, or mutations in РA gene responsible for baloxavir resistance. All viruses tested by fluorescence assay were sensitive to oseltamivir and zanamivir. The worldwide frequency of influenza isolates resistant to antineuraminidase drugs does not exceed 1-2% of cases. Hence, oseltamivir and zanamivir provide effective treatment for seasonal influenza.

Neuraminidase is an important target in the treatment of the influenza A virus. Screening natural neuraminidase inhibitors from medicinal plants is crucial for drug research. This study proposed a rapid strategy for identifying neuraminidase inhibitors from different crude extracts (Polygonum cuspidatum, Cortex Fraxini, and Herba Siegesbeckiae) using ultrafiltration combined with mass spectrometry guided by molecular docking. Firstly, the main component library of the three herbs was established, followed by molecular docking between the components and neuraminidase. Only the crude extracts with numbers of potential neuraminidase inhibitors identified by molecular docking were selected for ultrafiltration. This guided approach reduced experimental blindness and improved efficiency. The results of molecular docking indicated that the compounds in Polygonum cuspidatum demonstrated good binding affinity with neuraminidase. Subsequently, ultrafiltration‐mass spectrometry was employed to screen for neuraminidase inhibitors in Polygonum cuspidatum. A total of five compounds were fished out, and they were identified as trans‐polydatin, cis‐polydatin, emodin‐1‐O‐β‐D‐glucoside, emodin‐8‐O‐β‐D‐glucoside, and emodin. The enzyme inhibitory assay showed that they all had neuraminidase inhibitory effects. In addition, the key residues of the interaction between neuraminidase and fished compounds were predicted. In all, this study could provide a strategy for the rapid screening of the potential enzyme inhibitors from medicinal herbs. [ABSTRACT FROM AUTHOR]

In this study, we describe the input data and processing steps to find antiviral lead compounds by a virtual screen. Two-dimensional and three-dimensional filters were designed based on the X-ray crystallographic structures of viral neuraminidase co-crystallized with substrate sialic acid, substrate-like DANA, and four inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir). As a result, ligand–receptor interactions were modeled, and those necessary for binding were utilized as screen filters. Prospective virtual screening (VS) was carried out in a virtual chemical library of over half a million small organic substances. Orderly filtered moieties were investigated based on 2D- and 3D-predicted binding fingerprints disregarding the "rule-of-five" for drug likeness, and followed by docking and ADMET profiling. Two-dimensional and three-dimensional screening were supervised after enriching the dataset with known reference drugs and decoys. All 2D, 3D, and 4D procedures were calibrated before execution, and were then validated. Presently, two top-ranked substances underwent successful patent filing. In addition, the study demonstrates how to work around reported VS pitfalls in detail. [ABSTRACT FROM AUTHOR]

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Background: A stockpile of antiviral drugs is important for mitigating a novel influenza pandemic. Recently, intervention strategies against such a pandemic have improved significantly, affecting the required size and composition of the stockpile. Our goal is to estimate the optimal ratio of conventional to newer antiviral drugs. Method: We estimated epidemic parameters from daily-case data about H1N1pdm09 in the Republic of Korea, and used a deterministic ordinary differential equation model and stochastic simulation to predict the number of patients in a future pandemic. We considered an antiviral stockpile containing neuraminidase inhibitors (NAI) and a new drug, cap-dependent endonuclease inhibitor (CENI), seeking the optimum ratio of the two drugs under different epidemiological and economic assumptions. Results: With an effective reproductive number of 1.36, the expected cumulative cases did not exceed 30 % of the population in all vaccination scenarios. If the non-pharmaceutical intervention strategy is intensified and the effective reproductive number is decreased to 1.29, a 20 % antiviral stockpile of the population is sufficient. Assuming that CENI is prescribed for 10 % of patients, the expected total number of cases is decreased from 30 % to approximately 25 % of the population. If the cost of CENI is triple that of NAI, no expenditures beyond the current budget are necessary; if it is quintuple, expenditures increase by 17 %. Conclusion: Stockpiling CENI reduces the number of patients by reducing the infectious period. However, the government needs to consider the cost-effective stockpile ratio of such new drugs. This will depend not only on the cost of the drugs, but on factors difficult to anticipate, such as the transmissibility of the virus, the time needed for vaccine development, and (especially) the emergence of resistance. If this information can be estimated, our model can be used to obtain the optimum.

Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3–5 million severe cases of influenza are associated with 300 000–650 000 deaths per year globally. Antivirals effective at reducing morbidity and mortality are part of the first line of defense against influenza. FDA‐approved antiviral drugs currently include adamantanes (rimantadine and amantadine), neuraminidase inhibitors (NAI; peramivir, zanamivir, and oseltamivir), and the PA endonuclease inhibitor (baloxavir). Mutations associated with antiviral resistance are common and highlight the need for further improvement and development of novel anti‐influenza drugs. A summary is provided for the current knowledge of the approved influenza antivirals and antivirals strategies under evaluation in clinical trials. Preclinical evaluations of novel compounds effective against influenza in different animal models are also discussed.

In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54 /OSC and 54 /ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections. [Display omitted] • The PA-PB1 interaction inhibitor 54 acts synergistically with oseltamivir against influenza A and B viruses. • 54 and oseltamivir combined at low doses inhibit viral progeny production and proteins expression in cell culture. • 54 inhibits avian influenza virus replication both in cell culture and in embryonated chicken eggs. • 54 enhances oseltamivir protective effects in embryonated chicken eggs challenged with avian influenza virus. [ABSTRACT FROM AUTHOR]

Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010–2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor (baloxavir) were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC 50 s 3- to 4-fold lower than for other subtypes (median IC 50 : 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC 50 increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC 50 and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC 50 (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions. • The frequencies of markers of resistance to antiviral drugs were low among >20,000 avian influenza A viruses studied. • The A (H5Nx), A (H7Nx), and A (H9N2) viruses were susceptible to sub-nanomolar concentrations of antivirals. • NA-I222M, but not NA-S246N or NA-I222V, in avian influenza A (H5N1) viruses confers reduced inhibition by oseltamivir. • The previously unreported PA-A36T substitution reduces the susceptibility of A (H7Nx) and A (H9N2) subtypes to baloxavir. • PA-I38V, predominant in contemporary A (H9N2) viruses endemic to Egypt, does not reduce inhibition of viruses by baloxavir. [ABSTRACT FROM AUTHOR]

Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected cell to host cells. As such, neuraminidase has emerged as a pivotal target for mitigating influenza and its associated complications. Here, we apply a de novo hybridization approach based on a breed-centric methodology to elucidate novel neuraminidase inhibitors. The breed technique amalgamates established ligand frameworks with the shared target, neuraminidase, resulting in innovative inhibitor constructs. Molecular docking analysis revealed that the seven synthesized breed molecules (designated Breeds 1–7) formed more robust complexes with the neuraminidase receptor than conventional clinical neuraminidase inhibitors such as zanamivir, oseltamivir, and peramivir. Pharmacokinetic evaluations of the seven breed molecules (Breeds 1–7) demonstrated favorable bioavailability and optimal permeability, all falling within the specified parameters for human application. Molecular dynamics simulations spanning 100 nanoseconds corroborated the stability of these breed molecules within the active site of neuraminidase, shedding light on their structural dynamics. Binding energy assessments, which were conducted through MM-PBSA analysis, substantiated the enduring complexes formed by the seven types of molecules and the neuraminidase receptor. Last, the investigation employed a reaction-based enumeration technique to ascertain the synthetic pathways for the synthesis of the seven breed molecules.

Influenza remains one of the most common respiratory viral diseases with a high risk of complications. In the context of the COVID-19 pandemic, there is a possibility of simultaneous circulation of two viruses, which makes it necessary to conduct a differential diagnosis. Influenza and COVID-19 have common pathways of transmission of the pathogen and similar symptoms, so the optimal differential diagnosis is the use of test systems for both viruses. Against the background of influenza and COVID-19, complications from various organs and systems can develop. The article describes in detail the complications of influenza from the cardiovascular system. After infection with the flu virus, there is a 6-to 10-fold increase in the risk of acute myocardial infarction and a 3 - to 8-fold increase in the risk of stroke. COVID-19 is associated with arterial hypertension, diabetes mellitus, cardiac arrhythmias, myocarditis, high risk of acute myocardial infarction, and heart failure. The article presents the data of our own research, indicating that the transferred COVID-19 disease increases the risk of acute coronary syndrome, regardless of the presence of risk factors for cardiovascular events. Prevention of the development of influenza complications is the early administration of etiotropic antiviral therapy. Numerous studies confirm the effectiveness of the neuraminidase inhibitor oseltamivir in the treatment of influenza. The use of oseltamivir reduces the severity of clinical manifestations, reduces the duration of the disease, reduces the risk of complications and death. The most effective measure to prevent influenza and COVID-19 is specific immunization. In some cases, chemoprophylaxis can be used. The article discusses studies on the effectiveness of influenza chemoprophylaxis with the use of neuraminidase inhibitors.

To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization. [ABSTRACT FROM AUTHOR]

Aim: Graphene oxide (GO), known for its distinctive physicochemical properties, shows promise as a nanomaterial capable of combating infectious agents. This study investigates the efficacy of GO nanoparticles in restricting influenza A H1N1 replication in MDCK cells. Methods: GO nanoparticles were synthesized. After evaluating the toxicity of GO nanoparticles, the antiviral activity of the highest nontoxic concentration of GO against influenza A H1N1 in MDCK cells was studied. Results: GO treatments resulted in substantial decreases in virus titers, as shown via hemagglutination assay, TCID50 assay and real-time PCR analysis. Conclusion: This study emphasizes that GO nanoparticles have a high level of effectiveness against influenza A H1N1 viruses, making them an intriguing option for various antiviral uses.

The current work describes a fragment linking methodology to generate new neuraminidase inhibitors. A total number of 28,977 fragments from Zinc 20 have been obtained and screened for neuraminidase receptor affinity. Using Schrödinger software, the highest-scoring 270 fragment hits (with scores greater than -7.6) were subjected to fragment combining to create 100 new molecules. These 100 novel compounds were studied using XP docking to evaluate the molecular interaction modes and their binding affinity to neuraminidase receptor. The top ten molecules were selected, for ADMET, drug-likeness features. Based on these characteristics, the best four developed molecules and Zanamivir were submitted to a molecular dynamics simulation investigation to estimate their dynamics within the neuraminidase receptor using Gromacs software. All MD simulation findings show that the generated complexes are very stable when compared to the clinical inhibitor (Zanamivir). In addition, the four designed neuraminidase inhibitors formed very stable complexes with neuraminidase receptor (with total binding energies ranging from -83.50 to -107.85 Kj/mol) according to the total binding energy calculated by MM-PBSA. For the objective of developing new influenza medications, these novel molecules have the potential to be further evaluated in vitro and in vivo for influenza drug discovery.Communicated by Ramaswamy H. Sarma.

The influenza B virus is one of the causes of seasonal influenza, which has a long history of existence in various populations. Adolescents, children, pregnant women, the elderly, as well as patients with major diseases such as high blood pressure, diabetes, and cancer, and those with low immunity are more susceptible to infection by the influenza virus. During the influenza seasons, the influenza B virus can cause significant harm and economic burden. At present, neuraminidase inhibitors, hemagglutinin inhibitors and RNA polymerase inhibitors are the main antiviral drugs that are used in the clinical treatment of influenza B. Due to the repeated use of antiviral drugs in recent years, the emergence of resistant strains of the influenza virus exacerbated. By combining anti-viral drugs with different mechanisms of action or using a combination of traditional Chinese medicine and chemical drugs, the problem of reduced drug sensitivity can be improved. This article introduces the drug targets of the influenza B virus and the mechanism of virus resistance. It also emphasizes the clinically used antiviral drugs and their mechanisms of action, thereby providing a reference basis for the development of new anti-influenza drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Influenza is one of the most common infectious diseases and a significant public health problem. Every year, the influenza virus causes 3–5 million severe cases, millions hospitalizations and approximately 650,000 deaths. According to WHO four new influenza strains are projected to circulate in the 2020–2021 epidemic season. Influenza A and B strains are: A/Guangdong-Maonan/ SWL1536/2019 (H1N1) pdm09, A/Hong Kong/2671/2019 (H3N2), B/Washington/02/2019 (Victoria lineage), B/ Phuket/3073/2013 (Yamagata lineage). In this context, the problem of prescribing rational antiviral therapy is particularly importance. COVID-19, along with influenza, is a group of respiratory viral infections, but important differences exist in terms of viral agents and the spread of infection. Important differences include the rate of transmission. The average incubation period and generation time (the time between infecting one person and infecting another) for influenza are shorter. COVID-19 may be more severe, causing complications and deaths in 3–4% of cases. The estimated generation time for COVID 19 is 5-6 days, while for influenza it is 3 days. According to the latest data, the reproductive number, i.e., the number of people who can be infected by one patient, is in the range of 2 to 2.5 in COVID 19, which is higher than in influenza. Only a laboratory test can accurately identify the type of pathogen and distinguish it from influenza and other respiratory viruses. Neuraminidase inhibitors are currently first-line drugs recommended by WHO for the treatment and prevention of influenza.

Simple Summary: In this manuscript, we review research performed on enzymes called neuraminidases (NEUs) and the consequences of their activity on the heart muscle and on a few of its pathophysiological diseases. NEUs are able to cleave off sugars termed sialic acids, which are terminally attached to glycolipids and -proteins. Due to their outermost location, the level of sialic acids affects communication between cells, which in turn affects inflammatory responses. Thus, NEUs hold regulatory features influencing multiple processes within the body. The involvement of NEUs in cardiovascular pathologies i.e., atherosclerosis, myocardial infarction (MI), cardiomyopathies (CMs) and coronary artery disease (CAD) has been investigated and the activity of NEUs or rather the resulting sialic acid level has been identified as a diagnostic biomarker for cardiovascular disease. The downregulation of NEU activity in different animal models diminished inflammation, ameliorated cardiac function and improved vascular health, altogether identifying targeting NEU as a new promising treatment option for cardiac diseases. Fortunately, antiviral drugs blocking the activity of NEUs are already an established therapeutic regime in the treatment of influenza. First clinical trials using NEU inhibitor oseltamivir in patients with chronic heart failure are already ongoing. Glycoproteins and glycolipids on the cell surfaces of vertebrates and higher invertebrates contain α-keto acid sugars called sialic acids, terminally attached to their glycan structures. The actual level of sialylation, regulated through enzymatic removal of the latter ones by NEU enzymes, highly affects protein-protein, cell-matrix and cell-cell interactions. Thus, their regulatory features affect a large number of different cell types, including those of the immune system. Research regarding NEUs within heart and vessels provides new insights of their involvement in the development of cardiovascular pathologies and identifies mechanisms on how inhibiting NEU enzymes can have a beneficial effect on cardiac remodelling and on a number of different cardiac diseases including CMs and atherosclerosis. In this regard, a multitude of clinical studies demonstrated the potential of N-acetylneuraminic acid (Neu5Ac) to serve as a biomarker following cardiac diseases. Anti-influenza drugs i.e., zanamivir and oseltamivir are viral NEU inhibitors, thus, they block the enzymatic activity of NEUs. When considering the improvement in cardiac function in several different cardiac disease animal models, which results from NEU reduction, the inhibition of NEU enzymes provides a new potential therapeutic treatment strategy to treat cardiac inflammatory pathologies, and thus, administrate cardioprotection. [ABSTRACT FROM AUTHOR]

A stockpile of antiviral drugs is important for mitigating a novel influenza pandemic. Recently, intervention strategies against such a pandemic have improved significantly, affecting the required size and composition of the stockpile. Our goal is to estimate the optimal ratio of conventional to newer antiviral drugs. We estimated epidemic parameters from daily-case data about H1N1pdm09 in the Republic of Korea, and used a deterministic ordinary differential equation model and stochastic simulation to predict the number of patients in a future pandemic. We considered an antiviral stockpile containing neuraminidase inhibitors (NAI) and a new drug, cap-dependent endonuclease inhibitor (CENI), seeking the optimum ratio of the two drugs under different epidemiological and economic assumptions. With an effective reproductive number of 1.36, the expected cumulative cases did not exceed 30 % of the population in all vaccination scenarios. If the non-pharmaceutical intervention strategy is intensified and the effective reproductive number is decreased to 1.29, a 20 % antiviral stockpile of the population is sufficient. Assuming that CENI is prescribed for 10 % of patients, the expected total number of cases is decreased from 30 % to approximately 25 % of the population. If the cost of CENI is triple that of NAI, no expenditures beyond the current budget are necessary; if it is quintuple, expenditures increase by 17 %. Stockpiling CENI reduces the number of patients by reducing the infectious period. However, the government needs to consider the cost-effective stockpile ratio of such new drugs. This will depend not only on the cost of the drugs, but on factors difficult to anticipate, such as the transmissibility of the virus, the time needed for vaccine development, and (especially) the emergence of resistance. If this information can be estimated, our model can be used to obtain the optimum. [ABSTRACT FROM AUTHOR]

Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3-5 million severe cases of influenza are associated with 300 000-650 000 deaths per year globally. Antivirals effective at reducing morbidity and mortality are part of the first line of defense against influenza. FDA-approved antiviral drugs currently include adamantanes (rimantadine and amantadine), neuraminidase inhibitors (NAI; peramivir, zanamivir, and oseltamivir), and the PA endonuclease inhibitor (baloxavir). Mutations associated with antiviral resistance are common and highlight the need for further improvement and development of novel antiinfluenza drugs. A summary is provided for the current knowledge of the approved influenza antivirals and antivirals strategies under evaluation in clinical trials. Preclinical evaluations of novel compounds effective against influenza in different animal models are also discussed. [ABSTRACT FROM AUTHOR]

Purpose: Alerts for bleeding events are included in the Japanese package inserts of some anti‐influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti‐influenza drugs. This large‐scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti‐influenza drugs and in untreated patients. Methods: This retrospective cohort study used a large‐scale Japanese employment‐based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. Results: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti‐influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti‐influenza treatments (odds ratios for baloxavir were 0.90–0.99 compared to other therapies). Conclusions: Based on real‐world observation using a large‐scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti‐influenza drugs. [ABSTRACT FROM AUTHOR]

We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012 – 2013 and 2019 – 2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs. • We compared fever duration between baloxavir- and three NAIs-treated groups. • The study included 1742 patients aged <19 years during 2012–2020 in Japan. • For influenza A, fever duration in baloxavir- and NAIs-treated groups was similar. • For influenza B, fever duration was ∼15 h shorter in the baloxavir-treated group. [ABSTRACT FROM AUTHOR]