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Ki Hun Park - One of the best experts on this subject based on the ideXlab platform.

  • highly potent Bacterial Neuraminidase inhibitors chromenone derivatives from flemingia philippinensis
    International Journal of Biological Macromolecules, 2019
    Co-Authors: Yan Wang, Yeong Hun Song, Jeong Yoon Kim, Sang Hwa Yoon, Zia Uddin, Yeong Jun Ban, Keun Woo Lee, Ki Hun Park
    Abstract:

    Abstract The chromenone derivatives (1–4) from the root part of Flemingia philippinensis showed a significant inhibition against Bacterial Neuraminidase (NA) which plays a pivotal role in a cellular interaction including pathogenesis of Bacterial infection and subsequent inflammation. The compounds 1 and 2 were the new compounds, philippin D (1) and philippin E (2). In particular, compounds (1–3) exhibited sub micromolar levels of IC50 values with 0.75, 0.54, and 0.07 μM. This is the first report that chromenone skeleton emerged as a lead structure of Bacterial NA inhibition. In kinetic study, 8,8-diprenyl compounds displayed competitive inhibitory mode, whereas 4a,8-diprenyl ones showed noncompetitive behavior. It was manifested that all competitive inhibitors (1 and 2) were simple reversible slow-binding against Bacterial NA. The binding affinities (KSV) of inhibitors to enzyme were agreement with their respective inhibitory potencies. Molecular docking data confirmed that the position of 3-methyl-2-butenyl substituent affects inhibitory mechanism against CpNanI. The tri-arginyl cluster of R266, R555, and R615 and D291 in NanI tightly interact with the competitive inhibitors.

  • effectiveness of prenyl group on flavonoids from epimedium koreanum nakai on Bacterial Neuraminidase inhibition
    Molecules, 2019
    Co-Authors: Hong Min Choi, Jeong Yoon Kim, Yeong Jun Ban, Janar Jenis, Aizhamal Baiseitova, Ki Hun Park
    Abstract:

    In this study, the inhibitory potential of Bacterial Neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The methanol extraction process yielded eight flavonoids (1–8), of which compounds 7 and 8 were new compounds named koreanoside F and koreanoside G, respectively. All the compounds (1–8) showed a significant inhibition to Bacterial NA with IC50 values of 0.17–106.3 µM. In particular, the prenyl group on the flavonoids played a critical role in Bacterial NA inhibition. Epimedokoreanin B (compound 1, IC50 = 0.17 µM) with two prenyl groups on C8 and C5′ of luteolin was 500 times more effective than luteolin (IC50 = 85.6 µM). A similar trend was observed on compound 2 (IC50 = 0.68 µM) versus dihydrokaempferol (IC50 = 500.4 µM) and compound 3 (IC50 = 12.6 µM) versus apigenin (IC50 = 107.5 µM). Kinetic parameters (Km, Vmax, and Kik/Kiv) evaluated that all the compounds apart from compound 5 showed noncompetitive inhibition. Compound 5 was proven to be a mixed type inhibitor. In an enzyme binding affinity experiment using fluorescence, affinity constants (KSV) were tightly related to inhibitory activities.

  • Bacterial Neuraminidase inhibition by phenolic compounds from usnea longissima
    South African Journal of Botany, 2019
    Co-Authors: M Ullah, Z Uddin, Yeong Hun Song, Jeong Yoon Kim, Y J Ban, Ki Hun Park
    Abstract:

    Abstract Activity-guided phytochemical investigation of the methanol extract of Usnea longissima led to the isolation of nine (1–9) phenolic metabolites, including compounds 6 and 7, which were reported for the first time from this species. All isolated compounds were completely characterized through spectroscopic analysis, including 2D NMR and HREIMS data. Individually, the activity of each purified compound was assessed against Bacterial Neuraminidase (BNA), and most of them displayed dose-dependent inhibition. Among the purified compounds, compounds 2 and 3 exhibited significant inhibitory activities, with IC50 values of 7.8 and 8.2 μM, respectively, and had three-fold greater potency than the reference compound quercetin (IC50 = 21.4 μM). Furthermore, enzyme kinetics revealed that compounds 2 and 3 exhibited reversible and mixed type-I inhibitory behaviors, with inhibitory constant (Ki) values of 6.8 and 7.2 μM, respectively. Our results revealed the potential of U. longissima in inhibiting the enzyme BNA and highlighted its additional medicinal properties.

  • Effectiveness of Prenyl Group on Flavonoids from Epimedium koreanum Nakai on Bacterial Neuraminidase Inhibition
    MDPI AG, 2019
    Co-Authors: Hong Min Choi, Jeong Yoon Kim, Yeong Jun Ban, Janar Jenis, Aizhamal Baiseitova, Ki Hun Park
    Abstract:

    In this study, the inhibitory potential of Bacterial Neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The methanol extraction process yielded eight flavonoids (1–8), of which compounds 7 and 8 were new compounds named koreanoside F and koreanoside G, respectively. All the compounds (1–8) showed a significant inhibition to Bacterial NA with IC50 values of 0.17–106.3 µM. In particular, the prenyl group on the flavonoids played a critical role in Bacterial NA inhibition. Epimedokoreanin B (compound 1, IC50 = 0.17 µM) with two prenyl groups on C8 and C5′ of luteolin was 500 times more effective than luteolin (IC50 = 85.6 µM). A similar trend was observed on compound 2 (IC50 = 0.68 µM) versus dihydrokaempferol (IC50 = 500.4 µM) and compound 3 (IC50 = 12.6 µM) versus apigenin (IC50 = 107.5 µM). Kinetic parameters (Km, Vmax, and Kik/Kiv) evaluated that all the compounds apart from compound 5 showed noncompetitive inhibition. Compound 5 was proven to be a mixed type inhibitor. In an enzyme binding affinity experiment using fluorescence, affinity constants (KSV) were tightly related to inhibitory activities

  • potent Bacterial Neuraminidase inhibitors anthraquinone glucosides from polygonum cuspidatum and their inhibitory mechanism
    Journal of Ethnopharmacology, 2016
    Co-Authors: Zia Uddin, Yeong Hun Song, Jeong Yoon Kim, Marcus J Curtislong, Heung Joo Yuk, Ki Hun Park
    Abstract:

    Abstract Ethnopharmacological relevance P. cuspidatum is a popular Chinese medicinal herb, having a long history of usage in traditional Chinese medicine for the treatment of several inflammatory diseases in the form of powders and decoctions. Similarly there are many reports that P. cuspidatum has antiBacterial and anti-inflammatory effects, both of which are properties associated with compounds having activity against Bacterial Neuraminidase (BNA). Aim of the study We investigated whether P. cuspidatum's metabolites exhibited BNA inhibition. Consistent with our hypothesis, we found several inhibitors from the methanol extract of this plant, and then fully characterized their inhibitory mechanisms. Materials and methods Activity guided separation of methanol extract led to isolation of individual constituents, and subsequently their structures were elucidated by spectroscopic analysis. Detailed kinetic behaviors of BNA inhibitors were explored by showing the changes of Km and Vmax, the ratios of KI/KIS and Kik/Kiv, and fluorescence quenching effect. Results and conclusion This study attempted to isolate the responsible metabolites and elucidate the BNA inhibitory mechanism. The principal BNA inhibitory compounds (2–6) were identified as emodin (2), physcion-8-O-β- D -glucopyranoside (3), emodin-8-O-β- D -glucopyranoside (4), emodin-1-O-β- D -glucopyranoside (5), and 2-methoxy-6-acetyl-7-methyljuglone (6). Unexpectedly, anthraquinone glucosides (3–5) were much more potent than their corresponding aglycones (1 and 2). For example, emodin (2) had an IC50=5.4 μM, whereas its glucosides (4 and 5) had IC50=0.85 μM and 0.43 μM respectively. A similar trend was observed with physcion (1, IC50>200 μM) and its glucoside (3, IC50=6.2 μM). The anthraquinone (2) was mixed type I inhibitor, whereas its glucosides (4 and 5) were noncompetitive. In addition, the fluorescence quenching study showed that the affinity constants (KSV) of inhibitors increased in proportion to their inhibitory potencies. Furthermore, we quantified the major and minor metabolites through UPLC-PDA-Q-TOF/MS, and revealed that the most potent inhibitors were the major constituents. This result contributes to our understanding of P. cuspidatum utility as functional food stuff and widely used herbal medicine.

Garry L Taylor - One of the best experts on this subject based on the ideXlab platform.

  • structural studies on the pseudomonas aeruginosa sialidase like enzyme pa2794 suggest substrate and mechanistic variations
    Journal of Molecular Biology, 2009
    Co-Authors: Charlotte Ryan, Milton J Kiefel, Jennifer C Wilson, Garry L Taylor
    Abstract:

    Pseudomonas aeruginosa encodes an enzyme (PA2794) that is annotated as a sialidase (or Neuraminidase), as it possesses three Bacterial Neuraminidase repeats that are a signature of nonviral sialidases. A recent report showed that when the gene encoding this sialidase is knocked out, this led to a reduction in biofilm production in the lungs of mice, and it was suggested that the enzyme recognizes pseudaminic acid, a sialic acid analogue that decorates the flagella of Pseudomonas, Helicobacter, and Campylobacter species. Here, we present the crystal structure of the P. aeruginosa enzyme and show that it adopts a trimeric structure, partly held together by an immunoglobulin-like trimerization domain that is C-terminal to a classical beta-propeller sialidase domain. The recombinant enzyme does not show any sialidase activity with the standard fluorogenic sialic-acid-based substrate. The proposed active site contains certain conserved features of a sialidase: a nucleophilic tyrosine with its associated glutamic acid, and two of the usual three arginines that interact with the carboxylic acid group of the substrate, but is missing the first arginine and the aspartic acid that acts as an acid/base in all sialidases studied to date. We show, by in silico docking, that the active site may accommodate pseudaminic acid but not sialic acid and that this is due, in part, to a phenylalanine in the hydrophobic pocket that selects for the alternative stereochemistry of pseudaminic acid at C5 compared to sialic acid. Mutation of this phenylalanine to an alanine converts the enzyme into a sialidase, albeit a poor one, which we confirm by kinetics and NMR, and this allowed us to probe the function of other amino acids. We propose that a histidine plays the role of the acid/base, whose state is altered through a charge-relay system involving a novel His-Tyr-Glu triad. The location of this relay system precludes the presence of one of the three arginines usually found in a sialidase active site.

  • Structural Studies on the Pseudomonas aeruginosa Sialidase-Like Enzyme PA2794 Suggest Substrate and Mechanistic Variations
    Journal of Molecular Biology, 2009
    Co-Authors: Guogang Xu, Charlotte Ryan, Milton J Kiefel, Jennifer C Wilson, Garry L Taylor
    Abstract:

    Abstract Pseudomonas aeruginosa encodes an enzyme (PA2794) that is annotated as a sialidase (or Neuraminidase), as it possesses three Bacterial Neuraminidase repeats that are a signature of nonviral sialidases. A recent report showed that when the gene encoding this sialidase is knocked out, this led to a reduction in biofilm production in the lungs of mice, and it was suggested that the enzyme recognizes pseudaminic acid, a sialic acid analogue that decorates the flagella of Pseudomonas, Helicobacter, and Campylobacter species. Here, we present the crystal structure of the P. aeruginosa enzyme and show that it adopts a trimeric structure, partly held together by an immunoglobulin-like trimerization domain that is C-terminal to a classical β-propeller sialidase domain. The recombinant enzyme does not show any sialidase activity with the standard fluorogenic sialic-acid-based substrate. The proposed active site contains certain conserved features of a sialidase: a nucleophilic tyrosine with its associated glutamic acid, and two of the usual three arginines that interact with the carboxylic acid group of the substrate, but is missing the first arginine and the aspartic acid that acts as an acid/base in all sialidases studied to date. We show, by in silico docking, that the active site may accommodate pseudaminic acid but not sialic acid and that this is due, in part, to a phenylalanine in the hydrophobic pocket that selects for the alternative stereochemistry of pseudaminic acid at C5 compared to sialic acid. Mutation of this phenylalanine to an alanine converts the enzyme into a sialidase, albeit a poor one, which we confirm by kinetics and NMR, and this allowed us to probe the function of other amino acids. We propose that a histidine plays the role of the acid/base, whose state is altered through a charge-relay system involving a novel His-Tyr-Glu triad. The location of this relay system precludes the presence of one of the three arginines usually found in a sialidase active site.

  • contribution of the active site aspartic acid to catalysis in the Bacterial Neuraminidase from micromonospora viridifaciens
    FEBS Letters, 2004
    Co-Authors: Jacqueline N Watson, Garry L Taylor, Simon Newstead, Veedeeta Dookhun, Andrew J Bennet
    Abstract:

    A recombinant D92G mutant sialidase from Micromonospora viridifaciens has been cloned, expressed and purified. Kinetic studies reveal that the replacement of the conserved aspartic acid with glycine results in a catalytically competent retaining sialidase that possesses significant activity against activated substrates. The contribution of this aspartate residue to the free energy of hydrolysis for natural substrates is greater than 19 kJ/mol. The three dimensional structure of the D92G mutant shows that the removal of aspartic acid 92 causes no significant re-arrangement of the active site, and that an ordered water molecule substitutes for the carboxylate group of D92.

David Beighton - One of the best experts on this subject based on the ideXlab platform.

  • evidence for recombination between a sialidase nanh of actinomyces naeslundii and actinomyces oris previously named actinomyces naeslundii genospecies 1 and 2
    Fems Microbiology Letters, 2008
    Co-Authors: Uta Henssge, S C Gilbert, D T Clark, David Beighton
    Abstract:

    Actinomyces spp., predominant members of human oral biofilms, may use extracellular sialidase to promote adhesion, deglycosylate immunoglobulins and liberation of nutrients. Partial nanH gene sequences (1,077 bp) from Actinomyces oris (n=74), Actinomyces naeslundii (n=30), Actinomyces viscosus (n=1) and Actinomyces johnsonii (n=2) which included the active-site region and the Bacterial Neuraminidase repeats (BNRs) were compared. The sequences were aligned and each species formed a distinct cluster with five isolates having intermediate positions. These five isolates (two A. oris and three A. naeslundii) exhibited interspecies recombination. The nonsynonymous/synonymous ratio was <1 for both A. oris and A. naeslundii indicating that nanH in both species is under stabilizing selective pressure; nonsynonymous mutations are not selected. However, for A. oris significant negative values in tests for neutral selection suggested the rate of mutation in A. oris was greater than in A. naeslundii but with selection against nonsynonymous mutations. This was supported by the observation that the frequency of polymorphic sites in A. oris, which were monomorphic in A. naeslundii was significantly greater than the frequency of polymorphic sites in A. naeslundii which were monomorphic in A. oris (chi(2)=7.011; P=0.00081). The higher proportions of A. oris in the oral biofilm might be explained by the higher mutation rate facilitating an increased ability to respond successfully to environmental stress.

  • Evidence for recombination between a sialidase (nanH) of Actinomyces naeslundii and Actinomyces oris, previously named 'Actinomyces naeslundii genospecies 1 and 2'.
    Fems Microbiology Letters, 2008
    Co-Authors: Thuy Do, Uta Henssge, S C Gilbert, D T Clark, David Beighton
    Abstract:

    Actinomyces spp., predominant members of human oral biofilms, may use extracellular sialidase to promote adhesion, deglycosylate immunoglobulins and liberation of nutrients. Partial nanH gene sequences (1077 bp) from Actinomyces oris (n =74), Actinomyces naeslundii (n =30), Actinomyces viscosus (n =1) and Actinomyces johnsonii (n =2) which included the active-site region and the Bacterial Neuraminidase repeats (BNRs) were compared. The sequences were aligned and each species formed a distinct cluster with five isolates having intermediate positions. These five isolates (two A. oris and three A. naeslundii) exhibited interspecies recombination. The nonsynonymous/synonymous ratio was

Rik L. De Swart - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo
    2016
    Co-Authors: Ad Luijendijk, Albert D. M. E. Osterhaus, Paul W. Duprex, Rik L. De Swart
    Abstract:

    Human respiratory syncytial virus (HRSV) and Streptococcus pneumoniae are important causative agents of respiratory tract infections. Both pathogens are associated with season-al disease outbreaks in the pediatric population, and can often be detected simultaneously in infants hospitalized with bronchiolitis or pneumonia. It has been described that respiratory virus infections may predispose for Bacterial superinfections, resulting in severe disease. However, studies on the influence of Bacterial colonization of the upper respiratory tract on the pathogenesis of subsequent respiratory virus infections are scarce. Here, we have in-vestigated whether pneumococcal colonization enhances subsequent HRSV infection. We used a newly generated recombinant subgroup B HRSV strain that expresses enhanced green fluorescent protein and pneumococcal isolates obtained from healthy children in dis-ease-relevant in vitro and in vivomodel systems. Three pneumococcal strains specifically enhanced in vitro HRSV infection of primary well-differentiated normal human bronchial epi-thelial cells grown at air-liquid interface, whereas two other strains did not. Since previous studies reported that Bacterial Neuraminidase enhanced HRSV infection in vitro, we mea

  • streptococcus pneumoniae enhances human respiratory syncytial virus infection in vitro and in vivo
    PLOS ONE, 2015
    Co-Authors: Tien D Nguyen, Ad Luijendijk, Albert D. M. E. Osterhaus, Paul W. Duprex, Rogier Louwen, Karin Elberse, Geert Van Amerongen, Selma Yuksel, Rik L. De Swart
    Abstract:

    Human respiratory syncytial virus (HRSV) and Streptococcus pneumoniae are important causative agents of respiratory tract infections. Both pathogens are associated with seasonal disease outbreaks in the pediatric population, and can often be detected simultaneously in infants hospitalized with bronchiolitis or pneumonia. It has been described that respiratory virus infections may predispose for Bacterial superinfections, resulting in severe disease. However, studies on the influence of Bacterial colonization of the upper respiratory tract on the pathogenesis of subsequent respiratory virus infections are scarce. Here, we have investigated whether pneumococcal colonization enhances subsequent HRSV infection. We used a newly generated recombinant subgroup B HRSV strain that expresses enhanced green fluorescent protein and pneumococcal isolates obtained from healthy children in disease-relevant in vitro and in vivo model systems. Three pneumococcal strains specifically enhanced in vitro HRSV infection of primary well-differentiated normal human bronchial epithelial cells grown at air-liquid interface, whereas two other strains did not. Since previous studies reported that Bacterial Neuraminidase enhanced HRSV infection in vitro, we measured pneumococcal Neuraminidase activity in these cultures but found no correlation with the observed infection enhancement in our model. Subsequently, a selection of pneumococcal strains was used to induce nasal colonization of cotton rats, the best available small animal model for HRSV. Intranasal HRSV infection three days later resulted in strain-specific enhancement of HRSV replication in vivo. One S. pneumoniae strain enhanced HRSV both in vitro and in vivo, and was also associated with enhanced syncytium formation in vivo. However, neither pneumococci nor HRSV were found to spread from the upper to the lower respiratory tract, and neither pathogen was transmitted to naive cage mates by direct contact. These results demonstrate that pneumococcal colonization can enhance subsequent HRSV infection, and provide tools for additional mechanistic and intervention studies.

N. V. Kaverin - One of the best experts on this subject based on the ideXlab platform.

  • Phenotypic expression of HA-NA combinations in human-avian influenza A virus reassortants
    Archives of Virology, 1996
    Co-Authors: I. A. Rudneva, E. I. Sklyanskaya, O. S. Barulina, S. S. Yamnikova, V. P. Kovaleva, I. V. Tsvetkova, N. V. Kaverin
    Abstract:

    Human-avian and human-mammalian influenza A virus reassortant clones with the Neuraminidase (NA) gene of the A/USSR/90/77 (H1N1) strain and hemagglutinin (HA) genes of H3, H4 and H13 subtypes had been shown in an earlier publication to produce low HA yields in the embryonated chicken eggs. The low HA titers had been shown to be due, at least in part, to the formation of virion clusters at 4°C; the clustering was removed by the treatment with Bacterial Neuraminidase [Rudneva et al., Arch. Virol (1993) 133: 437–450]. By serial passages of the reassortants in chick embryos non-aggregating variants were selected: the variants produced HA titers of the same order as A/USSR/90/77 parent virus. The assessment of the virus yields by the analysis of the partially purified virus preparations from fixed volumes of the allantoic fluid revealed that actual virion yields of the initial reassortants were lower than the yields of their passaged variants or of the parent viruses. The passaged variant of a reassortant possessing the HA gene of A/Duck/Ukraine/1/63 (H3N2) virus differed from the original (non-passaged) reassortant and from the parent A/Duck/Ukraine/1/63 virus in the reaction with a panel of monoclonal antibodies against H3 hemagglutinin. The data suggest that some HA-NA combinations may lead to an incomplete functional match between HA and NA and to the formation of low-yield reassortants, thus representing a possible limiting factor in the emergence of new HA-NA combinations in natural conditions.

  • Influenza A virus reassortants with surface glycoprotein genes of the avian parent viruses: effects of HA and NA gene combinations on virus aggregation
    Archives of Virology, 1993
    Co-Authors: I. A. Rudneva, S. S. Yamnikova, V. P. Kovaleva, N. L. Varich, V. R. Farashyan, L. V. Gubareva, I. A. Popova, V. P. Presnova, N. V. Kaverin
    Abstract:

    A series of 33 human-avian and human-mammalian influenza virus reassortant clones possessing either HA or both HA and NA genes of the avian or mammalian virus was obtained by crosses of A/USSR/90/77 (H1N1) human virus with 5 avian and 1 mammalian influenza virus strains. All of the reasortants possessing NA genes of the H1N1 human parent virus and HA gene of an avian or mammalian parent virus had high values of infectivity/HA activity ratio. Since this feature could result from a limited virion aggregation, several reassortants were analyzed by velocity sucrose gradient centrifugation. In all cases tested, the reassortants of H3N1, H4N1, H10N1 and H13N1 composition were shown to be aggregated, whereas the preparations of the parent H1N1 virus and the reassortants possessing both HA and NA genes from the avian parents were represented mostly by single virions. The aggregates were formed at 4°C and dissociated at 37°C. The dissociation was blocked by an inhibitor of Neuraminidase activity (2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid). The dissociation was reversible since the virions reaggregated at 4°C; however, treatment with Bacterial Neuraminidase led to an irreversible dissociation of the aggregates. The tendency of the reassortants to aggregate correlates with an increased infectivity/HA ratio. No regular decrease in the Neuraminidase activity in the virions of reassortants as compared to the parent H1N1 virus was revealed. The most likely explanation of the observed phenomenon seems to be an inefficient removal of sialic acid residues from the avian virus hemagglutinin by the human virus N1 Neuraminidase.