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PubMed1977

Immobilized Clostridium perfringens neuraminidase. Substrate cleavage and enzyme release during incubation.

Pure Clostridium perfringens neuraminidase was immobilized on Sepharose 4 B, azido-Sepharose 4 B and controlled pore glass (CPG)- glycophase using different coupling procedures. The immobilized enzyme showed increased stability under various conditions relative to the soluble enzyme. The low release of active enzyme from the supports under incubation conditions was quantitated using a highly sensitive radioactive assay. The activity of the immobilized enzyme was dependent on the nature of the support and the substrate. Activity decreased with increasing substrate molecular weight, but the enzyme showed improved cleavage with GD1a micelles and human erythrocytes, substrates having ordered surface properties. Uses of immobilized neuraminidase in biochemistry and cell biology are considered and evaluated relative to the measured release of enzyme from the supports reported and to the molecular size and organization of possible substrates.

Azides↗
PubMed1978

Desialylation of glycoconjugates using immobilized vibrio cholerae neuraminidase. Preparation, properties and use of the bound enzyme.

Neuraminidase from Vibrio cholerae was immobilized on Sepharose 4B using the cyanogen bromide technique. The properties of the bound enzyme were found to be similar to those of the soluble form, except for an appreciably improved stability on storage at equivalent dilution and a reduction in recovered activity. Evidence was obtained that the binding of large molecular weight substrates to the bound enzyme is modified due to the immobilized state of the enzyme. The use of the enzyme gel for desialylation of glycoconjugates in a closed circuit system was investigated and optimal conditions delineated using fetuin as a model substrate. The bound enzyme could be used repeatedly with only low loss of activity. The value of the desialylation circuit in the preparation of partially and completely desialylated glycoconjugates is discussed. The use of immobilized neuraminidase for the desialylation of cells is described.

Drug Stability↗
PubMed1981

Purification and characterization of some enzymatic properties of neuraminidase from Corynebacterium ulcerans.

Neuraminidase of Corynebacterium-ulcerans was purified by affinity chromatography using immobilized colominic acid preparations. Neuraminidase appears to be a thermolabile protein, molecular mass 70 000 Da. The pH optimum of 5.5 is independent of the substrate used; the optimal temperature is 37 degrees C, the Michaelis constant towards N-acetylneuraminosyllactose is 5.2 X 10(-4) M. Ca2+ and Ba2+ activated the enzyme, but Zn2+, Fe2+, and chelating agent EDTA were inhibitory. In our experiments the enzyme did not hydrolyse the (alpha - 2.6) or (alpha - 2.8) bonds of submaxillary pig mucin and colominic acid, respectively, but it hydrolysed such substrates as fetuin, ovomucin, orosomucoid and horse serum glycoproteins.

Cations, Divalent↗
PubMed1977

A new marker for neuraminidase-treated human serum glycoproteins from the haemolymph of Tridacna maxima (Röding).

Highly purified human serum glycoproteins were treated with neuraminidase. The exposed subterminal carbohydrate structures reacted strongly with an anti-galactan precipitin from the haemolymph of Tridacna maxima which detects terminal, non-reducing beta-D-galactoside residues. This invertebrate precipitin, Tridacnin, may be used as a marker for nearly two thirds of all asialo serum glycoproteins; A number of different cross-reactions with various other polysaccharides and galactans subdivides those neuraminidase-treated glycoproteins into several subgroups, indicating that the uncovered carbohydrate structures are not always completely identical. In this way, together with the cross-reacting precipitins from plant and invertebrate origin. Tridacnin may be a useful tool for elucidating and establishing the structure of the carbohydrate part of serum glycoproteins.

Animals↗
PubMed2006

Safety of neuraminidase inhibitors for influenza.

Neuraminidase inhibitors, oseltamivir and zanamivir, are used for the treatment of, and protection from, influenza. The safety of these compounds has been assessed in systematic reviews. However, the data presented are somewhat limited by the paucity of good quality adverse event data available. The majority of safety outcomes are based on evidence from just one or two randomised controlled trials. The results of the systematic reviews suggest that neuraminidase inhibitors have a reasonable side effect and adverse effect profile if they are to be used to treat or protect patients against a life-threatening disease. However, if these compounds are to be prescribed in situations in which avoidance of inconvenience or minor discomfort is hoped for, then the balance of harms to benefits will be more difficult to judge.

Acetamides↗
PubMed2006

Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors.

Development of effective drugs for the treatment or prevention of epidemic and pandemic influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs available for influenza therapy currently. However, emergence of resistance to these drugs has been detected, which raises concerns regarding their widespread use. In this review, resistance to the adamantanes and neuraminidase inhibitors will be discussed in relation to both epidemic and pandemic influenza viruses.

Adamantane↗
PubMed2003

Assaying susceptibility of avian and other influenza A viruses to zanamivir: comparison of fluorescent and chemiluminescent neuraminidase assays.

Zanamivir has been shown to inhibit both human and avian influenza viral neuraminidases (NAs) and has been approved in several countries for the treatment and prophylaxis of influenza infection. Reliable monitoring of drug resistance is important for assessment of the impact of drug therapy on circulating virus populations. This study compares the current fluorometric (FL) method for evaluating zanamivir susceptibility with a recently developed chemiluminescent (CL) NA activity assay using viruses representative of all nine NA subtypes. The CL assay displayed signal/noise ratios that are 50-100 times greater than those associated with the FL assay. Human H3N2 strains appeared to exhibit greater NA activity relative to avian subtypes with the FL substrate but not with the CL substrate. Additionally, the CL assay remained linear over three orders of magnitude compared to only one order of magnitude for the FL assay. Four of the nine NA subtypes tested in this study displayed slightly higher inhibitor concentration that inhibits 50% of neuraminidase activity values by CL than by FL, while four displayed the opposite effect. Implications for the routine determination of resistance to NA inhibitors are discussed.

Animals↗
PubMed1998

New approaches to influenza chemotherapy. Neuraminidase inhibitors.

Epidemic influenza continues to be associated with significant morbidity in the general population, and mortality in the elderly and other high risk patients. Although the case fatality rate averages less than 0.01%, tens of thousands of deaths occur each year. Control through immunisation programmes has not been possible due to incomplete protective efficacy and antigenic variations that occur frequently. Currently available anti-influenza medications (amantadine and rimantadine) have had limited success due to underutilisation, lack of activity against influenza B, the rapid development of viral resistance to the drugs, and adverse effects. A new class of antiviral agents designed to inhibit influenza neuraminidase, an important surface glycoprotein, is currently under active development for use in the prophylaxis and treatment of influenza A and B infections. Two of these compounds, zanamivir (GG167) and GS4104 (the ethyl ester prodrug of GS4071) have reached clinical trials. Most studies of zanamivir have involved topical administration by inhalation of dry powder aerosols and/or intranasal doses of aqueous solutions. These routes rapidly provide high local concentrations at the sites of delivery. GS4104 is administered orally, which allows for greater ease of administration, and probably more uniform distribution of the parent compound GS4071 in the respiratory tract. Both have shown potent inhibitory activity against influenza in animal models and experimental human influenza with excellent tolerability profiles. Zanamivir treatment has been shown to reduce the severity and duration of naturally occurring, uncomplicated influenza illness in adults. Clinical resistance to these drugs has not been recognised as a significant problem to date, although strains resistant to each agent have been produced in the laboratory. This class of agents shows considerable promise as a novel approach to prophylaxis and treatment of influenza infections. Ongoing studies should provide the data needed to allow the addition of 1 or more of the neuraminidase inhibitors to the clinician's anti-influenza armamentarium.

Acetamides↗
PubMed2003

Neuraminidase inhibitors in pediatric patients: potential place in influenza therapy.

Influenza is responsible for annual epidemics, and is associated with significant morbidity and mortality. The development and use of antiviral agents is one of the recent strategies used to control influenza. Zanamivir and oseltamivir are members of a new class of antiviral agents, the neuraminidase inhibitors, that are effective in the treatment of influenza. These drugs have been evaluated in double-blind, placebo-controlled trials in children. Efficacy was shown by shortened duration of influenza-related symptoms in children treated with neuraminidase inhibitors. Seasonal prophylaxis in adults, and administration to household contacts of influenza-infected persons has decreased the incidence of influenza infection and illness. Adverse effects of zanamivir are minimal, while oseltamivir is associated with gastrointestinal upset, which does not usually require the medication to be ceased. No serious adverse events have been reported in children receiving these medications. Caution should be exercised in the use of zanamivir in children with asthma due to the potential development of bronchospasm and respiratory distress. Development of resistance to these medications is reported to occur less frequently than with amantadine. Resistance to zanamivir has been rarely detected during clinical trials, while up to 5.5% of influenza strains isolated from children after treatment were reported to be resistant to oseltamivir. Due to the role children play in the spread of influenza within the community, use of these medications may help control influenza epidemics.

Acetamides↗
PubMed1984

Adult type beta-galactosidase and neuraminidase deficiency in three siblings.

In recent years, there have been described a number of patients with beta-galactosidase and neuraminidase deficiency of juvenile onset. The clinical features in these patients are myoclonus, cherry-red spots, insidious visual loss, corneal clouding, gargoyle like appearance and ataxia. The condition appears to be transmitted as an autosomal recessive trait. Pathologically it has been characterized that there are vacuolation of lymphocytes, and inclusion bodies such as concentric membranous bodies in the ganglion cells of the rectum. Here we report a patient with beta-galactosidase and neuraminidase deficiency of juvenile onset in whom unusual "fingerprint" profiles were obtained in the submucosal ganglion cells in the rectum and will discuss the clinical significance of the inclusion bodies.

Humans↗
PubMed2000

Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor.

Rational drug design utilizing available X-ray crystal structures of sialic acid analogues bound to the active site of influenza virus neuraminidase has led to the discovery of a series of potent carbocyclic influenza neuraminidase inhibitors. From this series, GS 4104 (oseltamivir, TAMIFLU ) has emerged as a promising antiviral for the treatment and prophylaxis of human influenza infection. This article will summarize the design, discovery, and development of oseltamivir as an oral therapeutic to treat influenza infection.

Administration, Oral↗
PubMed2004

Controlling influenza by inhibiting the virus's neuraminidase.

Despite the fact that influenza is a disease which affects millions of people, sometimes with fatal consequences. there has not, until recently, been any drug effective against all strains. Vaccines may be relatively or totally ineffective, so drugs are needed. Random screening of many thousands of compounds by pharmaceutical companies has resulted in only two compounds, amantadine and rimantidine, which target the M2 ion channel on the virus. These drugs have major disadvantages. Knowledge of the crystal structure of influenza virus neuraminidase, on the other hand, has allowed the rational design of four "plug-drugs" which bind to the active site of flu neuraminidase and stop replication of the virus. Two of these compounds. Relenza and Tamiflu, are now being used worldwide and, although effective when used properly, suffer from problems of delivery. They need to be given very soon after infection to be effective, they only inhibit the influenza virus and none of the other respiratory agents which cause flu-like symptoms, and they are very expensive.

Animals↗
PubMed2006

Recent advances in anti-influenza agents with neuraminidase as target.

Neuraminidase (NA) is the major surface glycoprotein of the influenza virus. It has been considered a suitable target for designing agents against influenza viruses. Rational drug design of NA inhibitors is now in the clinic and is effective for the treatment of influenza. Recently, research of structure-based NA inhibitors is becoming an interesting field, leading to a breakthrough in the control of influenza. Here we review a series of neuraminidase inhibitors and the recent progress in this field.

Antiviral Agents↗
PubMed2006

Optimization of small molecule drugs binding to highly polar target sites: lessons from the discovery and development of neuraminidase inhibitors.

Binding affinity optimization of small molecules interacting with polar binding sites on target proteins is a formidable, but not uncommon challenge in drug discovery. The challenge relates to the difficulty of integrating favourable and unfavourable polar, non-polar and conformation contributions into overall favourable binding energies. This review describes the surprising breakthrough findings leading to the development of Tamiflu, a clinically efficacious orally bioavailable drug targeting the active site of influenza neuraminidase (NA). The NA active site is highly polar and formed mostly by arginine, aspartate and glutamate residues. This active site structure evolved for efficient interaction with charged sialic acid moieties on glycoproteins and stabilization of an oxocarbonium ion in the transition state of the neuraminidase reaction. The initial strategy of optimizing polar interactions in transition state analogs led to NA inhibitors (NAIs) with sub-nanomolar binding affinities, but such compounds were highly polar and lacked oral bioavailability. The realization of the possibility to achieve high affinity binding in a highly polar active site through optimization of non-polar and van-der-Waals interactions initially appeared counterintuitive and required a few serendipitous findings, but was key to reduce the polarity of drug candidates, avoid large desolvation penalties and achieve oral bioavailability.

Acetamides↗
PubMed1980

Hemagglutinin and neuraminidase specific cell-mediated immune responses to influenza A virus following immunization in guinea pigs.

Groups of guinea pigs were immunized with different inactivated recombinant influenza A viruses including H3ChN2Ch, Heq1N2Ch, H3ChNeq1 or uninfected allantoic fluid. Employing hemagglutination and neuraminidase inhibition tests, an in-vitro lymphocyte transformation (LTF) assay, and rosetting techniques for the separation of lymphocytes, influenza hemagglutinin (HA) and neuraminidase (NA) specific antibody and cell-mediated immune (CMI) responses were evaluated. Inactivated H3ChN2Ch, H3ChNeq1, HavN2Ch, and Heq1Neq1 recombinant influenza viruses were used as test antigens. Following immunization the CMI and antibody responses to influenza were characterized by the induction of specific LTF and antibody activity to homotypic HA or NA antigens but not to heterotypic HA or NA antigens. The temporal kinetics of the antibody response to influenza antigens was characterized by a prompt onset being initially detected at 1-2 weeks and reaching peak titers 3-4 weeks after immunization. Influenza specific LTF responses were first detected one week after immunization and declined to minimal responses at eight weeks. T-lymphocytes but not B-lymphocytes were capable of in-vitro recognition of the HA and NA antigens. After recognition the subsequent in-vitro lymphoproliferation was shown to involve both T and B lymphocytes.

Agglutinins↗
PubMed1975

Neuraminidase treated homologous IgG and immune deposit rental disease in inbred rats.

Immune deposit renal disease followed intravenous or intraperitoneal injections of neuraminidase treated homologous IgG or neuraminidase alone. No alterations were associated with several groups of controls. This preliminary study suggests that one mechanism by which microogranisms may be involved in the development of immune renal disease is by chemical alteration of immunoglobulin.

Animals↗
PubMed1975

The neuraminidase yield-reduction bioassay of human other interferons.

The production of neuraminidase by the recombinant influenza virus X7(F1) in human monkey, rabbit, hamster, mouse, and chicken cell cultures is inhibited by interferon. Described is a new enzyme assay for neuraminidase that can be applied to the bioassay of interferons. The advantages of this interferon bioassay are its sensitivity, reproducibility, rapidity, and convenience.

Animals↗