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PubMedDate not supplied

Experimental alteration of chinchilla middle ear mucosae by bacterial neuraminidase.

Streptococcus pneumoniae secretes a variety of extracellular glycosidase including a neuraminidase which has been found in middle ear effusion from patients with both acute and chronic otitis media. This enzyme cleaves sialic acid from membrane glycoproteins, thereby exposing galactose residues, the penultimate sugar. The ability of partially purified neuraminidase to alter the middle ear mucosa was investigated in the chinchilla. After incubation with neuraminidase, chinchilla middle ears were removed and exposed to galactose residues labeled with tritium. Membrane glycoproteins were solubilized and separated according to molecular weight by sodium dodecylsulfate electrophoresis. Increases in tritium incorporation, when compared to control incubations, indicated that galactose residues had been exposed and sialic acid residues removed from glycoproteins of both high and low molecular weight. Such membrane destruction could contribute significantly to the pathology of otitis media with effusion.

Animals↗

PubMed1983

Neuraminidase-activated attachment of Actinomyces naeslundii ATCC 12104 to human buccal epithelial cells.

The attachment of Actinomyces naeslundii ATCC 12104 to human buccal epithelial cells pre-treated with neuraminidase (sialidase) was evaluated. Both commercial clostridial neuraminidase and neuraminidase preparations from the test strain of A. naeslundii enhanced attachment. The results suggest that the A. naeslundii beta-galactoside-seeking ligand involved in hemagglutination and interbacterial coaggregation also mediates one type of binding to human buccal epithelial cells.

Actinomyces↗

PubMed2002

New millennium antivirals against pandemic and epidemic influenza: the neuraminidase inhibitors.

The mushroom shaped outer spike protein of influenza, neuraminidase, was first discovered nearly 60 years ago. Its importance in viral replication was soon recognised both at the point of viral release from the cell and also enabling passage of virus through nasal fluid to reach the cell. The enzyme active site was identified by x-ray crystallography, allowing an atomic study of interaction of enzyme with the sialic acid substrate. Analogues could then be identified and synthesized and became a focused target for antivirals. With the current threat of bioterrorism and the potential for the emergence of a new pandemic strain in the near future, efforts are underway to develop more potent second-generation anti-neuraminidase inhibitors with enhanced protective and therapeutic effects. Here we review older and newer neuraminidase inhibitors and the role that they will play in the fight against influenza in its epidemic and pandemic face.

Animals↗

PubMed1979

Immobilization of neuraminidase and its potential application in the modification of cell surfaces.

Vibrio cholerae neuraminidase was immobilized on the inside of 1.0 mm inner diameter nylon tubing with retention of enzyme activity, when assayed at 37 degrees C and pH 5.5 with mucin as substrate. The stabilities of the immobilized and soluble enzymes were similar for up to 3 hr at 37 degrees C. Preliminary data indicated that immobilized neuraminidase will release sialic acid from the surface of leukemic AKR mouse thymus and spleen lymphocytes; however, the level of immobilized enzyme activity needs to be increased for practical applications. With this improvement immobilized neuraminidase could become a novel preparation for carrying out cell surface modifications with minimal enzyme contamination of the cell.

Animals↗

PubMed1989

Glycoconjugates on corneal epithelial surface: effect of neuraminidase treatment.

The purpose of this study was to develop a procedure to quantitatively examine corneal epithelial apical cell membrane-associated glycoconjugates. Saccharide moieties on young, mature, and aged corneal epithelial cells were detected and localized in corneas of immature and adult mice by using colloidal gold-labeled lectins and transmission electron microscopy (TEM). In general, dense binding to the corneal epithelial apical surface cell membranes with wheat germ agglutinin (WGA) was seen in the adult, whereas the immature cornea bound less WGA-gold. Neuraminidase digestion decreased binding of the conjugate on epithelial plasma membranes of young and mature cells in adult cornea. Lectin-gold binding was decreased in the immature cornea on mature and aged cells. WGA-gold binding after neuraminidase was elevated on young cells of immature and on aged cells of adult animals. No binding of peanut agglutinin (PNA) or horse gram agglutinin (DBA) to the corneal epithelial surface was seen in animals of either age. After neuraminidase digestion, PNA binding sites were exposed only on the adult corneal surface. These data suggest that a terminal trisaccharide sequence, sialic acid-galactose beta(1----3)-N-acetylgalactosamine, is present at the adult corneal surface but is absent or at undetectable levels at the corneal surface of the immature animal. These data may be of significance in light of the dissimilar pattern of P. aeruginosa recognition and binding to the immature vs adult corneal epithelium.

Animals↗

PubMed1999

Reduction in the adherence of Pseudomonas aeruginosa to native cystic fibrosis epithelium with anti-asialoGM1 antibody and neuraminidase inhibition.

The high incidence of colonization of the cystic fibrosis (CF) airway with Pseudomonas aeruginosa has been attributed to several mechanisms including increased numbers of asialoglycolipid receptors, which may be further increased by exposure to the bacterial exoproduct, neuraminidase. This study examined whether the adherence of P. aeruginosa to fresh CF respiratory epithelial cells can be reduced in vitro by anti-asialoGM1 (anti-aGM1) antibody, neuraminidase inhibition, or the use of asialoGM1 tetrasaccharide as a competitive inhibitor. CF nasal epithelial cells were incubated with a nonmucoid strain of P. aeruginosa, in the presence or absence of a polyclonal anti-aGM1 antibody, the neuraminidase inhibitor 2,3-dehydro-2-deoxy-N-acetyl-neuraminic acid (DANA), or the tetrasaccharide moiety of aGM1. Adherence of bacteria to the apical surface of ciliated epithelial cells was quantified using scanning electron microscopy. Incubation of the cells with bacteria in the presence of either anti-aGM1 antibody or DANA significantly reduced bacterial adherence by 51(7)%, (p<0.01), and 34(9)%, (p<0.01), respectively. In contrast, no significant effect on P. aeruginosa binding was seen in the presence of aGM1 tetrasaccharide. The data are consistent with previous studies on cultured cells, and suggest that the in vivo effects of such interventions should be explored as potential mechanisms to reduce Pseudomonas aeruginosa colonization in cystic fibrosis.

Adult↗

PubMed1981

The effect of neuraminidase- and ribonuclease-susceptible surface anionic groups on the aggregation of embryonic chick neural retina cells.

The role of cell surface charge in cellular interactions has been the subject of conflicting reports. The major contribution to the net cell surface negativity of all mammalian cells studied is made by the sialic acid moieties of the surface glycoproteins, while ribonuclease-susceptible sites have been shown to contribute to the lesser extent on some cell types. Experiments were done to determine whether these anionic groups at the cell periphery affect the aggregation and sorting behaviour of embryonic chick neural retina cells when cultured alone or in combination with embryonic heart cells. The net negative surface charge density, as determined by cell electrophoretic mobility, of neuraminidase- or ribonuclease-treated cells was significantly decreased immediately after incubation with the enzymes, and the treatment with neuraminidase resulted in a reduction in the binding of colloidal iron hydroxide particles at the cell surface. Both enzymes caused reduced aggregate size in gyratory shaker cultures of neural retina and mixed cell suspensions, and fewer neural retina cells adherent to microtest plate surfaces, but no differences were seen in their histological appearance or sorting pattern in mixed shaker culture. The results indicate that the neuraminidase- and ribonuclease-susceptible groups at the periphery of embryonic neural retina cells play a role in some aspects of cell contact behaviour in ways other than reduction in net negative surface charge.

Animals↗

PubMed1983

Binding characteristics of 3H-dihydroalprenolol to beta-adrenoceptors of rat heart treated with neuraminidase.

Binding characteristics of the beta-blockers and beta-agonists with the beta-adrenoceptors were investigated in 3H-dihydroalprenolol (3H-DHA) binding to rat heart membranes treated with neuraminidase. When 60% of the total sialic acid content in the membranes was removed, reproducibility of the binding assay became much better than was attainable without neuraminidase treatment, and the maximum density of beta-adrenoceptors was increased. These data suggest that the binding of the test compounds with the beta-adrenergic receptors in cardiac muscle was under the influence of the sialic acid of the glycocalyx of the membrane. The 3H-DHA binding sites in membranes treated with neuraminidase showed a strict stereo-specificity when tested with propranolol. The ranking order of inhibition of beta-antagonists or agonists is: dl-propranolol greater than oxprenolol greater than alprenolol greater than pindolol greater than YM-09538 greater than labetalol greater than acebutolol greater than atenolol greater than metoprolol greater than sotalol greater than butoxamine greater than practolol as antagonists or l-isoproterenol greater than l-epinephrine greater than l-norepinephrine as agonists. A good correlation (r = 0.91, P less than 0.001) was observed between the Ki values observed by the present binding assay and the pA2 observed in the guinea-pig atria relative to the positive inotropic effect by Bieth et al. (Br. J. Pharmacol. 68, 563-569, 1980), indicating that the present method will be useful for screening new beta-adrenergic receptor antagonists or agonists.

Alprenolol↗

PubMed1986

Effects of deoxyribonuclease I and neuraminidase treatments on the specific binding of 3H-prazosin and 3H-quinuclidinyl benzilate (3H-QNB) to alpha-adrenergic and muscarinic receptors in rat myocardial membranes.

The effects of neuraminidase and deoxyribonuclease I (DNase) treatments on the specific binding of 3H-prazosin and 3H-quinuclidinyl benzilate (3H-QNB) to alpha-adrenoceptors and muscarinic cholinergic receptors in the membrane of the rat myocardium was examined, and the dissociation constant (Kd) and the maximum number of binding sites (Bmax) was analyzed using the method of Scatchard analysis. Although no changes in Kd values were observed when DNA or sialic acid was removed from cardiac muscles by treatments with DNase or neuraminidase, the Bmax values of alpha-adrenergic and muscarinic receptors were markedly decreased after treatment with DNase, while neuraminidase treatment induced an increase in the Bmax values of the alpha-adrenoceptors. The possibility that these results provide the basis for elucidation of the characteristics of these receptors in the rat myocardium was discussed.

Animals↗

PubMed2001

Neuraminidase inhibitors: zanamivir and oseltamivir.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of zanamivir and oseltamivir for the prophylaxis and treatment of influenza. DATA SOURCES: A MEDLINE search restricted to English-language journals was conducted (1980-May 2000). STUDY SELECTION AND DATA EXTRACTION: All efficacy and safety trials were included if conducted in humans and published in a journal. Abstracts were included if no other data source was available. DATA SYNTHESIS: Zanamivir and oseltamivir block influenza neuraminidase and prevent the cleavage of sialic acid residues, thus interfering with progeny virus dispersement within the mucosal secretions and reducing viral infectivity. The neuraminidase trials for prophylaxis and treatment of influenza enrolled predominantly young (mean age 29-37 y), healthy, mostly unvaccinated individuals who were at the lowest risk of influenza and its complications. When zanamivir 10 mg inhaled twice daily or oseltamivir 75 mg orally twice daily were used for treatment, systemic symptoms such as myalgias, fever, and headache were reduced by approximately 0.7-1.5 days. Greater efficacy (symptom reduction by 1.5-2.0 d) was noted in proven cases of influenza infection, in febrile patients, and in patients who received the treatment medication within 30 hours of symptom onset. Clinical efficacy did not increase when doses higher than the treatment dose approved by the Food and Drug Administration were used. When given for prophylaxis, zanamivir 10 mg inhaled once daily or oseltamivir 75 mg orally once daily was used for four to six weeks and achieved protective clinical efficacy for laboratory-confirmed influenza ranging from 67% to 74%, depending on whether culture or serologic tests were performed. The most common adverse effects (usually < 5%) included upper respiratory tract symptoms. Patients with asthma or chronic obstructive pulmonary disease who received zanamivir had an increased incidence of a > 20% decline in forced expiratory volume in one second or peak expiratory flow rates. Headaches, nausea, and vomiting were more frequent in the oseltamivir groups than in placebo groups. The most common gastrointestinal adverse effects, nausea and vomiting, were reduced to approximately 10% by administering the medication with food. CONCLUSIONS: Zanamivir and oseltamivir are more effective in preventing culture-positive influenza or for treatment of culture-positive influenza in febrile (> or = 37.8 degrees C) individuals. Treatment is more effective if initiated within 30 hours of symptom onset in febrile individuals; however, it is difficult to meet these criteria. More realistically, clinical efficacy is closer to 60-70% and, for treatment started within 48 hours for laboratory-confirmed influenza, symptom reduction is approximately 0.7-1.5 days. If used appropriately to minimize the development of resistance, the neuraminidase inhibitors represent a new and unique class of antiinfluenza agents that can potentially reduce the morbidity associated with influenza.

Acetamides↗

PubMed1977

Selective isolation of Vibrio cholerae neuraminidase using an immobilized 4-(nitrophenyl)oxamic acid.

N-(4-Nitrophenyl)oxamic acid[1] (1) was coupled with Sepharose 4B containing 1,6-diaminohexane as spacer group. This material was used as a specific adsorbent in the purification of Vibrio cholerae neuraminidase. The enzyme was completely retarded and separated from the bulk of the protein when washed with 50mM sodium acetate buffer, pH 5.0. A stepwise increase of sodium chloride concentration from 1.0 to 2.0M was found to be necessary for a sharp elution of neuraminidase activity. The purification was tenfold, and a recovery of more than 90% was obtained. Neuraminidase is only weakly retarded on a column of 1,6-diaminohexane coupled with Sepharose 4B and is not adsorbed by Sepharose 4B.

Chromatography, Affinity↗

PubMed1979

Properties and substrate specificities of two neuraminidases from Trichomonas fetus.

Trichomonas fetus, a protozoon belonging to the class of flagellates causes vaginal infections in cows, leading to sterility or abortion in early stage of pregnancy. Two neuraminidases were isolated from the culture medium and purified by various procedures of gel chromatography, ion exchange chromatography, and by affinity chromatography on N-(4-nitrophenyl)-oxamic acid-Sepharose 4B. The molecular weights of the two neuraminidases were determined as 320 000 (enzyme I) and 38 000 (enzyme II) respectively. However, enzyme I seems to consist of two isoenzymes containing four subunits of almost equal molecular weight. The pH optima of both enzymes depend on the substrates and range from pH 4.7 to 5.5. Due to the type of substrate, the Michaelis constants (Km) vary between 5.0 x 10(-2)M and 6.6 x 10(-3)M for enzyme I and between 1.4 x 10(-2)M and 4.9 x 10(-3)M for enzyme II. Among the different groups of NeuAc-containing substrates, i.e. glycoproteins, glycolipids, oligosaccharides and synthetic ketosides, enzyme I preferably cleaves high molecular weight glycoprotein type substrates whereas enzyme II shows higher affinities to low-molecular weight oligosaccharides. The ganglioside II3NeuAcGgOse4Cer is susceptible to both enzymes only after removal of the lipophilic ceramide residue. Both enzymes show differences in the specificity towards alpha 2 leads 3 to 3, alpha 2 leads to 6, and alpha 2 leads to 8 glycosidic linkages of NeuAc. Taking the rate of cleavage of the alpha 2 leads to linkage in II3NeuAc-Lac as 100, enzyme I reveals 65 for the alpha 2 leads to 6 linkage in II6NeuAc-Lac, and 15 for the alpha 2 leads to 8 linkage in II3(comes from 2 alpha NeuAc8)2-Lac, whereas enzyme II exhibits values around 50 for both the alpha 2 leads to 6- and the alpha 2 leads to 8-linked substrates. The activity of neuraminidase I and II is not influenced by Ca2 but is inhibited by Cu2, Hg2, ann 4-hydroxymercurisulfonic acid. The inhibition by Hg2 and by the latter is reversible with enzyme I by addition of dithioerythritol.

Animals↗

PubMed1982

Unmasking by neuraminidase of specific chorionic gonadotrophin binding activity of human placental syncytiotrophoblast.

Purified human placental syncytiotrophoblast consistently failed to bind specifically to 125I-labelled hCG. Treatment of the syncytiotrophoblast with neuraminidase resulted in the ability to bind 125I-labelled hCG that was displaceable by excess of unlabelled hCG. Neuraminidase treatment removed 73.8% of the total neuraminic acid of syncytiotrophoblast. The specific binding of 125I-labelled hCG increased linearly with increasing amount of neuraminidase-treated syncytiotrophoblast, was saturable and had a Ka = 1.6 x 10(7) M-1. Excess of GH, prolactin, placental lactogen or insulin did not inhibit the binding, whereas LH did so completely and FSH partly.

Chorionic Gonadotropin↗

PubMed2005

Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance.

Although influenza vaccination remains the primary method for the prevention of influenza, efficacy may be limited by a poor match between the vaccine and circulating strains and the poor response of elderly patients. Hence, there is an important role for antiviral therapy in the management of influenza. While amantadine and rimantadine have been available for the treatment of influenza in some countries for several years, they are only effective against influenza A viruses, they can have neurological and gastrointestinal adverse effects, and resistant virus is rapidly generated. Neuraminidase inhibitors, a new class of drug, are potent and specific inhibitors of all strains of influenza virus, and they have minimal adverse effects. The greatest benefit is seen in those patients presenting <30 hours after development of influenza symptoms, those with severe symptoms or those in high-risk groups. In addition to treatment of the infection, both drugs are effective prophylactically and have been shown to limit spread of infection in close communities, such as families and in nursing homes. No resistant virus strains have been isolated from normal individuals treated with zanamivir. Resistant virus can be isolated from approximately 1% of adults and 5% of paediatric patients with influenza treated with oseltamivir. However, infectivity of mutant viruses is generally compromised. Governments spend millions of dollars on influenza vaccination campaigns; however, once influenza virus is circulating in the community, vaccination cannot limit the spread of disease. A greater promotion of the use of neuraminidase inhibitors for the treatment and prevention of influenza could have a significant impact on limiting its spread. This could result in saving millions of dollars, not only in direct costs associated with medical and hospital care, but also significant savings in indirect costs associated with the loss of productivity at work, school and home environments. For the benefit of all communities, there needs to be a greater awareness of the symptoms of influenza and the efficacy of neuraminidase inhibitors in disease treatment.

Acetamides↗

PubMed2005

Neuraminidase inhibitors as antiviral agents.

The enzyme neuraminidase (NA) is an attractive target for antiviral strategy because of its essential role in the pathogenicity of many respiratory viruses. NA removes sialic acid from the surface of infected cells and virus particles, thereby preventing viral self-aggregation and promoting efficient viral spread; NA also plays a role in the initial penetration of the mucosal lining of the respiratory tract. Random screening for inhibitors has identified only low-affinity and nonselective viral NA inhibitors. Selective, high-affinity inhibitors of influenza virus neuraminidase, zanamivir and oseltamivir, were developed using computer-aided design techniques on the basis of the three-dimensional structure of the influenza virus NA. These drugs were highly efficient in inhibiting replication of both influenza A and B viruses in vitro and in vivo and were approved for human use in 1999. Subsequently, the same structure-based design approach was used for the rational design of inhibitors of the parainfluenza virus hemagglutinin-neuraminidase (HN). One of these compounds, BCX 2798, effectively inhibited NA activity, cell binding, and growth of parainfluenza viruses in tissue culture and in the lungs of infected mice. Clinical reports indicate high efficiency of NA inhibitors for prophylaxis and treatment of influenza virus infection, good tolerance, and a low rate of emergence of drug-resistant mutants. Future experimental and clinical studies should establish the viability of NA inhibitors for the treatment of other respiratory virus infections.

Acetamides↗

PubMed2003

Surveillance for neuraminidase inhibitor resistance in human influenza viruses from Australia.

Two hundred and forty-five human influenza A and B viruses isolated in Australia between 1996 and 2003 were tested for their sensitivity to the NA inhibitor drugs, zanamivir and oseltamivir using a fluorescence-based neuraminidase inhibition assay. Based on mean IC50 values, influenza A viruses (with neuraminidase subtypes N1 and N2) were more sensitive to both the NA inhibitors than were influenza B strains. Influenza A viruses with a N1 subtype and influenza B strains both demonstrated a greater sensitivity to zanamivir than to oseltamivir carboxylate, whereas influenza A strains with a N2 subtype were more susceptible to oseltamivir carboxylate. A comparison of IC50 values for viruses isolated before and after the release of the NA inhibitors in Australia, found there was no significant difference in the sensitivity of strains to either neuraminidase inhibitor and none of the isolates tested showed clinically significant resistance.

Acetamides↗

PubMed1984

Decreased fertility resulting from treatment of fowl spermatozoa with neuraminidase or phospholipase c.

The effect of altering the surface topography of fowl spermatozoal plasma membranes on subsequent fertilizing ability was studied by exposing Single Comb White Leghorn spermatozoa to neuraminidase or phospholipase c. Semen was diluted 1:1 with Beltsville Poultry Semen Extender (BPSE) or BPSE containing 40 IU/ml neuraminidase or 100 IU/ml phospholipase c, then incubated 30 min at 25 C before intravaginal insemination. Incubation of spermatozoa with either enzyme did not reduce motility or lyse spermatozoa as monitored by glutamate oxaloacetate transaminase release. However, fertility was depressed by neuraminidase or phospholipase c, 54 and 4%, respectively, compared to 88% for the incubated control. Intravaginal deposition of enzyme solutions 30 min prior to insemination with BPSE diluted semen did not affect fertility. This study demonstrates that alteration of carbohydrate and phospholipid moieties of the spermatozoal plasma membrane decreases fertility without reducing motility.

Animals↗

PubMed1976

[Inhibiting effect of cholera vibrio neuraminidase in Rauscher mouse leukemia].

A study was made of the inhibitory effect of neuraminidase of cholera vibrio in mouse Rauscher leukemia. It was shown that the processing of cells of the spleen of mice suffering from leukemia with neuraminidase (in a dose of 50 units/ml and more) significantly inhibited the capacity of these cells to induce leukemia in their injection to BALB/c mice. In the mentioned concentration neuraminidase injected repeatedly parenterally produced no therapeutic effect in Rauscher leukemia.

Animals↗