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1
Hammond, Alexandria J., Ulrike Binsker, Surya D. Aggarwal, Mila Brum Ortigoza, Cynthia Loomis, and Jeffrey N. Weiser. "Neuraminidase B controls neuraminidase A-dependent mucus production and evasion." PLOS Pathogens 17, no. 4 (April 5, 2021): e1009158. http://dx.doi.org/10.1371/journal.ppat.1009158.
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Binding of Streptococcus pneumoniae (Spn) to nasal mucus leads to entrapment and clearance via mucociliary activity during colonization. To identify Spn factors allowing for evasion of mucus binding, we used a solid-phase adherence assay with immobilized mucus of human and murine origin. Spn bound large mucus particles through interactions with carbohydrate moieties. Mutants lacking neuraminidase A (nanA) or neuraminidase B (nanB) showed increased mucus binding that correlated with diminished removal of terminal sialic acid residues on bound mucus. The non-additive activity of the two enzymes raised the question why Spn expresses two neuraminidases and suggested they function in the same pathway. Transcriptional analysis demonstrated expression of nanA depends on the enzymatic function of NanB. As transcription of nanA is increased in the presence of sialic acid, our findings suggest that sialic acid liberated from host glycoconjugates by the secreted enzyme NanB induces the expression of the cell-associated enzyme NanA. The absence of detectable mucus desialylation in the nanA mutant, in which NanB is still expressed, suggests that NanA is responsible for the bulk of the modification of host glycoconjugates. Thus, our studies describe a functional role for NanB in sialic acid sensing in the host. The contribution of the neuraminidases in vivo was then assessed in a murine model of colonization. Although mucus-binding mutants showed an early advantage, this was only observed in a competitive infection, suggesting a complex role of neuraminidases. Histologic examination of the upper respiratory tract demonstrated that Spn stimulates mucus production in a neuraminidase-dependent manner. Thus, an increase production of mucus containing secretions appears to be balanced, in vivo, by decreased mucus binding. We postulate that through the combined activity of its neuraminidases, Spn evades mucus binding and mucociliary clearance, which is needed to counter neuraminidase-mediated stimulation of mucus secretions.
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Jost, B. H., J. G. Songer, and S. J. Billington. "Cloning, Expression, and Characterization of a Neuraminidase Gene from Arcanobacterium pyogenes." Infection and Immunity 69, no. 7 (July 1, 2001): 4430–37. http://dx.doi.org/10.1128/iai.69.7.4430-4437.2001.
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ABSTRACT Arcanobacterium pyogenes is an opportunistic pathogen, associated with suppurative infections in domestic animals. In addition to pyolysin, a pore-forming, cholesterol-binding toxin,A. pyogenes expresses a number of putative virulence factors, including several proteases and neuraminidase activity. A 3,009-bp gene, nanH, was cloned and sequenced and conferred neuraminidase activity on an Escherichia colihost strain. The predicted 107-kDa NanH protein displayed similarity to a number of bacterial neuraminidases and contained the RIP/RLP motif and five copies of the Asp box motif found in all bacterial neuraminidases. Recombinant His-tagged NanH was found to have pH and temperature optima of 5.5 to 6.0 and 55°C, respectively. Insertional deletion of the nanH gene resulted in the reduction, but not absence, of neuraminidase activity, indicating the presence of a second neuraminidase gene in A. pyogenes. NanH was localized to the A. pyogenes cell wall. A. pyogenes adhered to HeLa, CHO, and MDBK cells in a washing-resistant manner. However, the nanH mutant was not defective for adherence to epithelial cells. The role of NanH in host epithelial cell adherence may be masked by the presence of a second neuraminidase in A. pyogenes.
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Manco, Sonia, Fidelma Hernon, Hasan Yesilkaya, James C. Paton, Peter W. Andrew, and Aras Kadioglu. "Pneumococcal Neuraminidases A and B Both Have Essential Roles during Infection of the Respiratory Tract and Sepsis." Infection and Immunity 74, no. 7 (July 2006): 4014–20. http://dx.doi.org/10.1128/iai.01237-05.
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ABSTRACT We examined the role of the neuraminidases NanA and NanB in colonization and infection in the upper and lower respiratory tract by Streptococcus pneumoniae, as well as the role of these neuraminidases in the onset and development of septicemia following both intranasal and intravenous infection. We demonstrated for the first time using outbred MF1 mouse models of infection that both NanA and NanB were essential for the successful colonization and infection of the upper and lower respiratory tract, respectively, as well as pneumococcal survival in nonmucosal sites, such as the blood. Our studies have shown that in vivo a neuraminidase A mutant is cleared from the nasopharynx, trachea, and lungs within 12 h postinfection, while a neuraminidase B mutant persists but does not increase in either the nasopharynx, trachea, or lungs. We also demonstrated both neuraminidase mutants were unable to cause sepsis following intranasal infections. When administered intravenously, however, both mutants survived initially but were unable to persist in the blood beyond 48 h postinfection and were progressively cleared. The work presented here demonstrates the importance of pneumococcal neuraminidase A and for the first time neuraminidase B in the development of upper and lower respiratory tract infection and sepsis.
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Jost, B. Helen, J. Glenn Songer, and Stephen J. Billington. "Identification of a Second Arcanobacterium pyogenes Neuraminidase and Involvement of Neuraminidase Activity in Host Cell Adhesion." Infection and Immunity 70, no. 3 (March 2002): 1106–12. http://dx.doi.org/10.1128/iai.70.3.1106-1112.2002.
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ABSTRACT Arcanobacterium pyogenes, a common inhabitant of the upper respiratory and urogenital tracts of economically important animals, such as cattle and swine, is also an opportunistic pathogen associated with suppurative infections in these animals. A. pyogenes expresses neuraminidase activity encoded by the nanH gene, and previously, construction of a nanH mutant of A. pyogenes BBR1 indicated that a second neuraminidase is present in this strain. A 5,112-bp gene, nanP, was cloned and sequenced, and this gene conferred neuraminidase activity on an Escherichia coli host strain. The predicted 186.8-kDa NanP protein exhibited similarity to a number of bacterial neuraminidases and contained the RIP/RLP motif and five copies of the Asp box motif found in all bacterial neuraminidases. As expected, insertional inactivation of the nanP gene in A. pyogenes BBR1 resulted in a mutant with reduced neuraminidase activity. However, insertional inactivation of the nanP gene in the nanH mutant strain resulted in a complete lack of neuraminidase activity. Like NanH, NanP was localized to the A. pyogenes cell wall. However, unlike the nanH gene, which was present in 100% of the strains examined, nanP was present in only 64.2% of the isolates (n = 53). A. pyogenes adheres to HeLa cells, and a nanP mutant displayed a wild-type adhesion phenotype with these cells. In contrast, the ability of a nanH nanP double mutant to bind to HeLa cells was reduced by 53%. The wild-type adhesion phenotype was restored by providing nanP in trans. These data indicate that the neuraminidases of A. pyogenes play a role in adhesion of this organism to host epithelial cells.
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Teuton, Jeremy R., and Curtis R. Brandt. "Sialic Acid on Herpes Simplex Virus Type 1 Envelope Glycoproteins Is Required for Efficient Infection of Cells." Journal of Virology 81, no. 8 (January 17, 2007): 3731–39. http://dx.doi.org/10.1128/jvi.02250-06.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) envelope proteins are posttranslationally modified by the addition of sialic acids to the termini of the glycan side chains. Although gC, gD, and gH are sialylated, it is not known whether sialic acids on these envelope proteins are functionally important. Digestion of sucrose gradient purified virions for 4 h with neuraminidases that remove both α2,3 and α2,6 linked sialic acids reduced titers by 1,000-fold. Digestion with a α2,3-specific neuraminidase had no effect, suggesting that α2,6-linked sialic acids are required for infection. Lectins specific for either α2,3 or α2,6 linkages blocked attachment and infection to the same extent. In addition, the mobility of gH, gB, and gD in sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels was altered by digestion with either α2,3 specific neuraminidase or nonspecific neuraminidases, indicating the presence of both linkages on these proteins. The infectivity of a gC-1-null virus, ΔgC2-3, was reduced to the same extent as wild-type virus after neuraminidase digestion, and attachment was not altered. Neuraminidase digestion of virions resulted in reduced VP16 translocation to the nucleus, suggesting that the block occurred between attachment and entry. These results show for the first time that sialic acids on HSV-1 virions play an important role in infection and suggest that targeting virion sialic acids may be a valid antiviral drug development strategy.
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Baeza-Kallee, Nathalie, Raphaël Bergès, Victoria Hein, Stéphanie Cabaret, Jeremy Garcia, Abigaëlle Gros, Emeline Tabouret, Aurélie Tchoghandjian, Carole Colin, and Dominique Figarella-Branger. "Deciphering the Action of Neuraminidase in Glioblastoma Models." International Journal of Molecular Sciences 24, no. 14 (July 19, 2023): 11645. http://dx.doi.org/10.3390/ijms241411645.
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Glioblastoma (GBM) contains cancer stem cells (CSC) that are resistant to treatment. GBM CSC expresses glycolipids recognized by the A2B5 antibody. A2B5, induced by the enzyme ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyl transferase 3 (ST8Sia3), plays a crucial role in the proliferation, migration, clonogenicity and tumorigenesis of GBM CSC. Our aim was to characterize the resulting effects of neuraminidase that removes A2B5 in order to target GBM CSC. To this end, we set up a GBM organotypic slice model; quantified A2B5 expression by flow cytometry in U87-MG, U87-ST8Sia3 and GBM CSC lines, treated or not by neuraminidase; performed RNAseq and DNA methylation profiling; and analyzed the ganglioside expression by liquid chromatography–mass spectrometry in these cell lines, treated or not with neuraminidase. Results demonstrated that neuraminidase decreased A2B5 expression, tumor size and regrowth after surgical removal in the organotypic slice model but did not induce a distinct transcriptomic or epigenetic signature in GBM CSC lines. RNAseq analysis revealed that OLIG2, CHI3L1, TIMP3, TNFAIP2, and TNFAIP6 transcripts were significantly overexpressed in U87-ST8Sia3 compared to U87-MG. RT-qPCR confirmed these results and demonstrated that neuraminidase decreased gene expression in GBM CSC lines. Moreover, neuraminidase drastically reduced ganglioside expression in GBM CSC lines. Neuraminidase, by its pleiotropic action, is an attractive local treatment against GBM.
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Stadlbauer, Daniel, Xueyong Zhu, Meagan McMahon, Jackson S. Turner, Teddy J. Wohlbold, Aaron J. Schmitz, Shirin Strohmeier, et al. "Broadly protective human antibodies that target the active site of influenza virus neuraminidase." Science 366, no. 6464 (October 24, 2019): 499–504. http://dx.doi.org/10.1126/science.aay0678.
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Better vaccines against influenza virus are urgently needed to provide broader protection against diverse strains, subtypes, and types. Such efforts are assisted by the identification of novel broadly neutralizing epitopes targeted by protective antibodies. Influenza vaccine development has largely focused on the hemagglutinin, but the other major surface antigen, the neuraminidase, has reemerged as a potential target for universal vaccines. We describe three human monoclonal antibodies isolated from an H3N2-infected donor that bind with exceptional breadth to multiple different influenza A and B virus neuraminidases. These antibodies neutralize the virus, mediate effector functions, are broadly protective in vivo, and inhibit neuraminidase activity by directly binding to the active site. Structural and functional characterization of these antibodies will inform the development of neuraminidase-based universal vaccines against influenza virus.
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Mohan, Sankar, and B. Mario Pinto. "Exploration of the 150 cavity and the role of serendipity in the discovery of inhibitors of influenza virus A neuraminidase." Canadian Journal of Chemistry 96, no. 2 (February 2018): 91–101. http://dx.doi.org/10.1139/cjc-2017-0343.
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Influenza pandemics are an ongoing threat for the human population, as the avian influenza viruses H5N1 and H7N9 continue to circulate in the bird population and the chance of avian to human transmission increases. Neuraminidase, a glycoprotein located on the surface of the influenza virus, plays a crucial role in the viral replication process and, hence, has proven to be a useful target enzyme for the treatment of influenza infections. The discovery that certain subtypes of influenza neuraminidase have an additional cavity, the 150 cavity, near the substrate binding site has triggered considerable interest in the design of influenza inhibitors that exploit this feature. Currently available antiviral drugs, neuraminidase inhibitors oseltamivir and zanamivir, were designed using crystal structures predating this discovery by some years. This mini review is aimed at summarizing our group’s efforts, together with related work from other groups, on neuraminidase inhibitors that are designed to exploit both the catalytic site and the 150 cavity. The design of a parent scaffold that yields a potent inhibitor that is active in cell culture assays and retains activity against several neuraminidases from mutant strains is also described. Finally, the role of serendipity in the discovery of a new class of potent neuraminidase inhibitors with a novel spirolactam scaffold is also highlighted.
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Zhang, Jun-Yuan, Qian-Qian Chen, Jia Li, Lei Zhang, and Lian-Wen Qi. "Neuraminidase 1 and its Inhibitors from Chinese Herbal Medicines: An Emerging Role for Cardiovascular Diseases." American Journal of Chinese Medicine 49, no. 04 (January 2021): 843–62. http://dx.doi.org/10.1142/s0192415x21500403.
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Neuraminidase, also known as sialidase, is ubiquitous in animals and microorganisms. It is predominantly distributed in the cell membrane, cytoplasmic vesicles, and lysosomes. Neuraminidase generally recognizes the sialic acid glycosidic bonds at the ends of glycoproteins or glycolipids and enzymatically removes sialic acid. There are four types of neuraminidases, named as Neu1, Neu2, Neu3, and Neu4. Among them, Neu1 is the most abundant in mammals. Recent studies have revealed the involvement of Neu1 in several diseases, including cardiovascular diseases, diabetes, cancers, and neurological disorders. In this review, we center the attention to the role of Neu1 in cardiovascular diseases, including atherosclerosis, ischemic myocardial injury, cerebrovascular disease, congenital heart disease, and pulmonary embolism. We also summarize inhibitors from Chinese herbal medicines (CHMs) in inhibiting virus neuraminidase or human Neu1. Many Chinese herbs and Chinese herb preparations, such as Lonicerae Japonicae Flos, Scutellariae Radix, Yupingfeng San, and Huanglian Jiedu Decoction, have neuraminidase inhibitory activity. We hope to highlight the emerging role of Neu1 in humans and potentially titillate interest for further studies in this area.
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Hall, B. F., P. Webster, A. K. Ma, K. A. Joiner, and N. W. Andrews. "Desialylation of lysosomal membrane glycoproteins by Trypanosoma cruzi: a role for the surface neuraminidase in facilitating parasite entry into the host cell cytoplasm." Journal of Experimental Medicine 176, no. 2 (August 1, 1992): 313–25. http://dx.doi.org/10.1084/jem.176.2.313.
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Trypanosoma cruzi enters host cells via formation of an acidic vacuole which is subsequently disrupted, allowing the parasite access to the cytoplasm. We show that in an acid environment, release of the parasite surface neuraminidase is enhanced, and this release is likely mediated by a phosphatidylinositol-specific phospholipase C (PIPLC), since antibodies to a carbohydrate epitope (CRD) revealed in glycosylphosphatidylinositol (GPI)-anchored proteins after PIPLC cleavage remove the great majority of the soluble neuraminidase activity from culture supernatants. The neuraminidase is active at acidic pH, and is capable of desialylating known vacuolar constituents, i.e., lysosomal membrane glycoproteins. Parasite escape into the cytoplasm is significantly facilitated in terminal sialylation-defective mutant Lec 2 cells, and enzymatically desialylated membranes are more susceptible to lysis by a parasite hemolysin previously implicated in vacuole membrane rupture. These findings provide evidence that terminal sialylation on carbohydrate moieties contributes to maintaining lysosomal membrane integrity, and indicate a role for a protozoan-derived neuraminidase in facilitating parasite entry into host cells. These observations raise the possibility that other microbial neuraminidases may serve a similar function in acidic intracellular compartments.
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Porotto, Matteo, Olga Greengard, Natalia Poltoratskaia, Maria-Arantxa Horga, and Anne Moscona. "Human Parainfluenza Virus Type 3 HN-Receptor Interaction: Effect of 4-Guanidino-Neu5Ac2en on a Neuraminidase-Deficient Variant." Journal of Virology 75, no. 16 (August 15, 2001): 7481–88. http://dx.doi.org/10.1128/jvi.75.16.7481-7488.2001.
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ABSTRACT The envelope of human parainfluenza virus type 3 (HPF3) contains two viral glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). HN, which is responsible for receptor attachment and for promoting F-mediated fusion, also possesses neuraminidase (receptor-destroying) activity. We reported previously that 4-guanidino-neu5Ac2en (4-GU-DANA) and related sialic acid-based inhibitors of HPF3 neuraminidase activity also inhibit HN-mediated receptor binding and fusion processes not involving neuraminidase activity. We have now examined this mechanism, as well as neuraminidase's role in the viral life cycle, using a neuraminidase-deficient HPF3 variant (C28a) and stable cell lines expressing C28a or wild-type (wt) HN. C28a, which has a wt F sequence and two point mutations in the HN gene corresponding to two amino acid changes in the HN protein, is the first HPF3 variant with insignificant neuraminidase activity. Cells expressing C28a HN did not bind erythrocytes at 4°C unless pretreated with neuraminidase, but no such pretreatment was required for hemadsorption activity (HAD) at 22 or 37°C. HAD was blocked by 4-GU-DANA, attesting to the ability of this compound to inhibit HN's receptor-binding activity. C28a or wt plaque enlargement, a process that involves cell-cell fusion and does not depend on virion release, is diminished by the presence of 4-GU-DANA, confirming the inhibitory effect of 4-GU-DANA on the fusogenic function of C28a HN. In C28a-infected cell monolayers, virion release and thus multicycle replication are severely restricted. This defect was corrected by supplementation of exogenous neuraminidase and also by the addition of 4-GU-DANA; neuraminidase destroys the receptors whereby newly formed C28a virions would remain attached to the cell surface, whereas 4-GU-DANA prevents the attachment itself, obviating the need for receptor cleavage. In accord with the ability of 4-GU-DANA to prevent attachment, the neuraminidase inhibitory effect of 4-GU-DANA on wt HPF3 did not diminish virion release into the medium. Thus, it is by inhibition of viral entry and syncytium formation that sialic acid analogs like 4-GU-DANA may counteract wt HPF3 infection.
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Bantia, S., C. D. Parker, S. L. Ananth, L. L. Horn, K. Andries, P. Chand, P. L. Kotian, et al. "Comparison of the Anti-Influenza Virus Activity of RWJ-270201 with Those of Oseltamivir and Zanamivir." Antimicrobial Agents and Chemotherapy 45, no. 4 (April 1, 2001): 1162–67. http://dx.doi.org/10.1128/aac.45.4.1162-1167.2001.
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ABSTRACT We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design. In this paper, we compare the potency of three compounds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all tested influenza A and influenza B neuraminidases in vitro, with 50% inhibitory concentrations of 0.09 to 1.4 nM for influenza A neuraminidases and 0.6 to 11 nM for influenza B neuraminidases. These values were comparable to or lower than those for oseltamivir carboxylate (GS4071) and zanamivir (GG167). RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influenza virus neuraminidase over mammalian, bacterial, or other viral neuraminidases. Oral administration of a dosage of 1 mg/kg of body weight/day of RWJ-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the murine model of influenza virus infection as determined by lethality and weight loss protection. RWJ-270201 administered intranasally at 0.01 mg/kg/day in the murine influenza model demonstrated complete protection against lethality, whereas oseltamivir carboxylate and zanamivir at the same dose demonstrated only partial protection. In the delayed-treatment murine influenza model, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamivir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant protection against lethality (P < 0.001 versus control). However, when the treatment was delayed for 48 h, no significant protection was observed in either drug group. No drug-related toxicity was observed in mice receiving 100 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles justify further consideration of RWJ-270201 for the treatment and prevention of human influenza.
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Tai, Chun Y., Paul A. Escarpe, Robert W. Sidwell, Matthew A. Williams, Willard Lew, Huiwei Wu, Choung U. Kim, and Dirk B. Mendel. "Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071." Antimicrobial Agents and Chemotherapy 42, no. 12 (December 1, 1998): 3234–41. http://dx.doi.org/10.1128/aac.42.12.3234.
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ABSTRACT An oral prodrug of GS 4071, a potent and selective inhibitor of influenza neuraminidases, is currently under clinical development for the treatment and prophylaxis of influenza virus infections in humans. To investigate the potential development of resistance during the clinical use of this compound, variants of the human influenza A/Victoria/3/75 (H3N2) virus with reduced susceptibility to the neuraminidase inhibitor GS 4071 were selected in vitro by passaging the virus in MDCK cells in the presence of inhibitor. After eight passages, variants containing two amino acid substitutions in the hemagglutinin (A28T in HA1 and R124M in HA2) but no changes in the neuraminidase were isolated. These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay. After 12 passages, a second variant containing these hemagglutinin mutations and a Lys substitution for the conserved Arg292 of the neuraminidase was isolated. The mutant neuraminidase enzyme exhibited high-level (30,000-fold) resistance to GS 4071, but only moderate (30-fold) resistance to zanamivir and 4-amino-Neu5Ac2en, the amino analog of zanamivir. The mutant enzyme had weaker affinity for the fluorogenic substrate 2′-(4-methylumbelliferyl)-α-d- N -acetylneuraminic acid and lower enzymatic activity compared to the wild-type enzyme. The viral variant containing the mutant neuraminidase did not replicate as well as the wild-type virus in culture and was 10,000-fold less infectious than the wild-type virus in a mouse model. These results suggest that although the R292K neuraminidase mutation confers high-level resistance to GS 4071 in vitro, its effect on viral virulence is likely to render this mutation of limited clinical significance.
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Colman, Peter M. "A novel approach to antiviral therapy for influenza." Journal of Antimicrobial Chemotherapy 44, suppl_2 (November 1, 1999): 17–22. http://dx.doi.org/10.1093/jac/44.suppl_2.17.
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Abstract The influenza glycoprotein, neuraminidase, destroys sialic acid–containing receptors on the surface of infected cells and on progeny virions. This activity facilitates the elution of newly budded virus from the infected cell surface and thus contributes to the viral burden in the host. On the basis of the three–dimensional structure of neuraminidase and the structure of the enzyme—product complex, novel analogues of the product (sialic acid, Neu5Ac) were designed and were shown to be potent inhibitors of neuraminidase in vitro and in vivo. Zanamivir (4–guanidino–Neu5Ac2en) is one of the most potent of the sialic acid analogues described to date. It is broadly inhibitory of all type A and B neuraminidases, probably because one of its design features was the requirement that it should interact only with strain–invariant amino acids inside the active site of the enzyme. Inhibition of neuraminidase translates into antiviral activity in tissue culture, in animal models of influenza and in both experimental and naturally acquired influenza in humans. Zanamivir is a minimal modification of the natural ligand (Neu5Ac) of the enzyme. This feature is expected to minimize the viability of drug–resistant virus that might arise through mutations in the enzyme active site. Studies to date of drug–resistant variants selected in tissue culture confirm this expectation. To deliver zanamivir directly to the lungs of patients the agent has been formulated for inhalation using a modified Diskhaler, which ensures high local concentrations and maximizes inhibition of viral neuraminidase.
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Guo, X., and M. L. Sinnott. "Salmonella typhimurium neuraminidase acts with inversion of configuration." Biochemical Journal 296, no. 2 (December 1, 1993): 291–92. http://dx.doi.org/10.1042/bj2960291.
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When the time course of the hydrolysis of identical solutions of p-nitrophenyl N-acetyl-alpha-D-neuraminide by Salmonella typhimurium neuraminidase is monitored by u.v. and by its optical rotation, the rotation change is synchronous with, or even marginally in advance of, the absorbance change. In experiments under the same conditions with influenza-virus neuraminidase, known to react with retention of configuration [Chong, Pegg, Taylor and von Itzstein (1992) Eur. J. Biochem. 207, 335-343], the rotation change is much slower than the absorbance change. The inverting, presumably single-displacement, mode of action of the S. typhimurium enzyme follows from these observations, and the position (92.5% beta) of the slowly established mutarotational equilibrium of N-acetylneuraminic acid [Friebolin, Kunzelmann, Supp, Brossmer, Keilich and Ziegler (1981) Tetrahedron Lett. 22, 1383-1386].
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Monto, Arnold S., Jennifer L. McKimm-Breschkin, Catherine Macken, Alan W. Hampson, Alan Hay, Alexander Klimov, Masato Tashiro, et al. "Detection of Influenza Viruses Resistant to Neuraminidase Inhibitors in Global Surveillance during the First 3 Years of Their Use." Antimicrobial Agents and Chemotherapy 50, no. 7 (July 2006): 2395–402. http://dx.doi.org/10.1128/aac.01339-05.
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ABSTRACT Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) develops at a low level following drug treatment, and person-to-person transmission of resistant virus has not been recognized to date. The Neuraminidase Inhibitor Susceptibility Network (NISN) was established to follow susceptibility of isolates and occurrence of NAI resistance at a population level in various parts of the world. Isolates from the WHO influenza collaborating centers were screened for susceptibilities to oseltamivir and zanamivir by a chemiluminescent enzyme inhibition assay, and those considered potentially resistant were analyzed by sequence analysis of the neuraminidase genes. During the first 3 years of NAI use (1999 to 2002), 2,287 isolates were tested. Among them, eight (0.33%) viruses had a >10-fold decrease in susceptibility to oseltamivir, one (0.22%) in 1999 to 2000, three (0.36%) in 2000 to 2001, and four (0.41%) in 2001 to 2002. Six had unique changes in the neuraminidase gene compared to neuraminidases of the same subtype in the influenza sequence database. Although only one of the mutations had previously been recognized in persons receiving NAIs, none were from patients who were known to have received the drugs. During the 3 years preceding NAI use, no resistant variants were detected among 1,054 viruses. Drug use was relatively stable during the period, except for an approximate 10-fold increase in oseltamivir use in Japan during the third year. The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use.
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Bonten, Erik J., and Alessandra d'Azzo. "Lysosomal Neuraminidase." Journal of Biological Chemistry 275, no. 48 (September 11, 2000): 37657–63. http://dx.doi.org/10.1074/jbc.m007380200.
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Air, Gillian M. "Influenza neuraminidase." Influenza and Other Respiratory Viruses 6, no. 4 (November 16, 2011): 245–56. http://dx.doi.org/10.1111/j.1750-2659.2011.00304.x.
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Nguyen, Hoai Viet, Katerina Tmejova, Ludmila Krejcova, David Hynek, Pavel Kopel, Jindrich Kynicky, Vojtech Adam, and Rene Kizek. "Neuraminidase Gene." International Journal of Electrochemical Science 9, no. 7 (July 2014): 3364–73. http://dx.doi.org/10.1016/s1452-3981(23)08015-x.
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Ferraris, Olivier, and Bruno Lina. "Mutations of neuraminidase implicated in neuraminidase inhibitors resistance." Journal of Clinical Virology 41, no. 1 (January 2008): 13–19. http://dx.doi.org/10.1016/j.jcv.2007.10.020.
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Mikurova, A. V., A. V. Rybina, and V. S. Skvortsov. "Prediction of selective inhibition of neuraminidase from various influenza virus strains by potential inhibitors." Biomeditsinskaya Khimiya 62, no. 6 (2016): 691–703. http://dx.doi.org/10.18097/pbmc20166206691.
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A universal model of inhibition of neuraminidases from various influenza virus strains by a particular has been developed. It is based on known 3D data for neuraminidases from three influenza virus strains (A/Tokyo/3/67, A/tern/Australia/G70C/75, B/Lee/40) and modeling of 3D structure of neuraminidases from other strains (A/PR/8/34 and A/Aichi/2/68). Using docking and molecular dynamics, we have modeled 235 enzyme-ligand complexes for 185 compounds with known IC50 values. Selection of final variants among three results obtained for each enzyme-ligand pair and calculation of independent variables for generation of linear regression equations was performed using MM-PBSA/MM-GBSA. This resulted in the set of equations individual strains and the equations pooling all the data. Thus using this approach it is possible to predict inhibition for neuraminidase from each of the considered strains by a particular inhibitor and to predict the range of its action on neuraminidases from various influenza virus strains.
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Cavallesco, R., and M. E. Pereira. "Antibody to Trypanosoma cruzi neuraminidase enhances infection in vitro and identifies a subpopulation of trypomastigotes." Journal of Immunology 140, no. 2 (January 15, 1988): 617–25. http://dx.doi.org/10.4049/jimmunol.140.2.617.
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Abstract A rabbit antibody to the neuraminidase of the infective form of Trypanosoma cruzi identifies a subpopulation of trypomastigotes that expresses neuraminidase. Complement-mediated lysis by the antibody selectively destroys 30 to 40% of the trypomastigotes, supporting the conclusion that the immune antibody binds to a subset of parasites. The trypomastigotes that react with the immune antibody are the only ones expressing neuraminidase because the trypomastigotes that survive complement-mediated lysis are depleted of neuraminidase activity. The enzyme seems to negatively modulate infection in vitro, since infection of host cells by trypomastigotes is enhanced when neuraminidase activity is blocked by antineuraminidase antibody; infection is also enhanced when the infecting trypomastigotes have been depleted of parasites that express neuraminidase. Addition of exogenous neuraminidase (from Vibrio cholerae) to trypomastigotes treated with immune antibody, reverts the enhancement observed when infection takes place in the presence of antibody to T. cruzi neuraminidase only. Addition of V. cholerae neuraminidase in the absence of immune antibodies has no effect on infection. These results show that T. cruzi neuraminidase depresses infection and also suggest that sialic acid is involved in the parasite-host cell interaction. The antibody to T. cruzi neuraminidase recognizes on the surface of live trypomastigotes a set of proteins with high m.w. (165,000 to 200,000) and also two antigens of 79,000 to 82,000. The high m.w. proteins appear to be associated with neuraminidase activity as shown by renaturation experiments of released enzyme fractionated on a sodium dodecyl sulfate-polyacrylamide gel.
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Campbell, Ashley C., John J. Tanner, and Kurt L. Krause. "Optimisation of Neuraminidase Expression for Use in Drug Discovery by Using HEK293-6E Cells." Viruses 13, no. 10 (September 22, 2021): 1893. http://dx.doi.org/10.3390/v13101893.
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Influenza virus is a highly contagious virus that causes significant human mortality and morbidity annually. The most effective drugs for treating influenza are the neuraminidase inhibitors, but resistance to these inhibitors has emerged, and additional drug discovery research on neuraminidase and other targets is needed. Traditional methods of neuraminidase production from embryonated eggs are cumbersome, while insect cell derived protein is less reflective of neuraminidase produced during human infection. Herein we describe a method for producing neuraminidase from a human cell line, HEK293-6E, and demonstrate the method by producing the neuraminidase from the 1918 H1N1 pandemic influenza strain. This method produced high levels of soluble neuraminidase expression (>3000 EU/mL), was enhanced by including a secretion signal from a viral chemokine binding protein, and does not require co-expression of additional proteins. The neuraminidase produced was of sufficient quantity and purity to support high resolution crystal structure determination. The structure solved using this protein conformed to the previously reported structure. Notably the glycosylation at three asparagine residues was superior in quality to that from insect cell derived neuraminidase. This method of production of neuraminidase should prove useful in further studies, such as the characterisation of inhibitor binding.
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Long, J. P., H. H. Tong, and T. F. DeMaria. "Immunization with Native or Recombinant Streptococcus pneumoniae Neuraminidase Affords Protection in the Chinchilla Otitis Media Model." Infection and Immunity 72, no. 7 (July 2004): 4309–13. http://dx.doi.org/10.1128/iai.72.7.4309-4313.2004.
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ABSTRACT Streptococcus pneumoniae neuraminidase has been implicated as a virulence factor in the pathogenesis of pneumococcal otitis media. In this study, native neuraminidase was partially purified from cultures of S. pneumoniae by serial chromatography with DEAE-Sepharose and Sephacryl S-200. Recombinant neuraminidase, a 3,038-bp fragment of the neuraminidase A (nanA) gene, was cloned into the pET-28b vector and then expressed at high levels in Escherichia coli. Chinchillas were immunized subcutaneously with either the gel-purified native or recombinant neuraminidase, and all responded with elevated titers of antineuraminidase antibody in serum. Immunization with neuraminidase resulted in a significant reduction in nasopharyngeal colonization as well as in the incidence of otitis media with effusion. These data demonstrate for the first time that neuraminidase affords protection against S. pneumoniae nasopharyngeal colonization and experimental otitis media.
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Liu, Zekun, Junpeng Zhao, Weichen Li, Xinkun Wang, Jingxuan Xu, Jin Xie, Ke Tao, Li Shen, and Ran Zhang. "Molecular Docking of Potential Inhibitors for Influenza H7N9." Computational and Mathematical Methods in Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/480764.
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As a new strain of virus emerged in 2013, avian influenza A (H7N9) virus is a threat to the public health, due to its high lethality and pathogenicity. Furthermore, H7N9 has already generated various mutations such as neuraminidase R294K mutation which could make the anti-influenza oseltamivir less effective or ineffective. In this regard, it is urgent to develop new effective anti-H7N9 drug. In this study, we used the general H7N9 neuraminidase and oseltamivir-resistant influenza virus neuraminidase as the acceptors and employed the small molecules including quercetin, chlorogenic acid, baicalein, and oleanolic acid as the donors to perform the molecular docking for exploring the binding abilities between these small molecules and neuraminidase. The results showed that quercetin, chlorogenic acid, oleanolic acid, and baicalein present oseltamivir-comparable high binding potentials with neuraminidase. Further analyses showed that R294K mutation in neuraminidase could remarkably decrease the binding energies for oseltamivir, while other small molecules showed stable binding abilities with mutated neuraminidase. Taken together, the molecular docking studies identified four potential inhibitors for neuraminidase of H7N9, which might be effective for the drug-resistant mutants.
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López, José Agustín, Antonio José Maldonado, Marlene Gerder, José Abanero, Juan Murgich, Flor H. Pujol, Ferdinando Liprandi, and Juan Ernesto Ludert. "Characterization of Neuraminidase-Resistant Mutants Derived from Rotavirus Porcine Strain OSU." Journal of Virology 79, no. 16 (August 15, 2005): 10369–75. http://dx.doi.org/10.1128/jvi.79.16.10369-10375.2005.
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ABSTRACT Infection by some rotavirus strains requires the presence of sialic acid on the cell surface, its infectivity being reduced in cells treated with neuraminidase. A neuraminidase treatment-resistant mutant was isolated from the porcine rotavirus strain OSU. In reassortant strains, the neuraminidase-resistant phenotype segregated with the gene coding for VP4. The mutant retained its capacity to bind to sialic acid. The VP4 sequence of the mutant differed from that of the parental OSU strain in an Asp-to-Asn substitution at position 100. Neutralization escape mutants selected from an OSU neuraminidase-sensitive clone by monoclonal antibodies that failed to recognize the neuraminidase-resistant mutant strain carried the same mutation at position 100 and were also neuraminidase resistant. Neuraminidase sensitivity was restored when the mutation at position 100 was compensated for by a second mutation (Gln to Arg) at position 125. Molecular mechanics simulations suggest that the neuraminidase-resistant phenotype associated with mutation of OSU residue 100 from Asp to Asn reflects the conformational changes of the sialic acid cleft that accompany sialic acid binding.
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Mikurova, A. V., A. V. Rybina, and V. S. Skvortsov. "Prediction of inhibition of influenza virus neuraminidase of various strains by using a generalized model constructed using the data on the position of known ligands." Biomeditsinskaya Khimiya 66, no. 6 (2020): 508–13. http://dx.doi.org/10.18097/pbmc20206606508.
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Several variants of models for predicting the IC50 values of inhibitors of influenza virus neuraminidase are presented for both individual strains and for combinations of data for neuraminidases of several strains. They are based on the use of calculated energy contributions to the amount of change in the free energy of enzyme-inhibitor complexes. In contrast to previous works, aimed at the complex modeling, we added a procedure of comparison of the docking variants with one of the neuraminidase inhibitors, for which the structure of the complexes was determined experimentally. The choice of the comparison structure was made according to the similarity of structures evaluated using the Tanimoto metrics and the limit of the RMSD value for a similar part of the structure was no more than 2 Å. Using this limitation and filtering datasets for a particular strain by the Q2 value obtained in the leave-one-out control procedure it is possible to construct equations for predicting the IC50 value with a Q2 value close to the minimum confidence threshold (0.57 in this work). Taking into consideration that in this version of the prediction, a minimum set of energy contributions is used, which does not provide for expensive calculations of entropy contributions, the result obtained supports the correctness of using a generalized model based on the data on the position of known ligands to predict the inhibition of neuraminidase of the influenza virus of various strains.
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Fox, Annette, and Louise Carolan. "Neuraminidase escape attempts." Nature Microbiology 4, no. 12 (November 21, 2019): 2031–32. http://dx.doi.org/10.1038/s41564-019-0615-2.
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Osherovich, Lev. "Trapping influenza neuraminidase." Science-Business eXchange 6, no. 11 (March 2013): 254. http://dx.doi.org/10.1038/scibx.2013.254.
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Garcia-Sastre, A. "The neuraminidase of bat influenza viruses is not a neuraminidase." Proceedings of the National Academy of Sciences 109, no. 46 (October 25, 2012): 18635–36. http://dx.doi.org/10.1073/pnas.1215857109.
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Sehnert, Bettina, Juliane Mietz, Rita Rzepka, Stefanie Buchholz, Andrea Maul-Pavicic, Sandra Schaffer, Falk Nimmerjahn, and Reinhard E. Voll. "Neuraminidase Inhibitor Zanamivir Ameliorates Collagen-Induced Arthritis." International Journal of Molecular Sciences 22, no. 3 (January 31, 2021): 1428. http://dx.doi.org/10.3390/ijms22031428.
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Altered sialylation patterns play a role in chronic autoimmune diseases such as rheumatoid arthritis (RA). Recent studies have shown the pro-inflammatory activities of immunoglobulins (Igs) with desialylated sugar moieties. The role of neuraminidases (NEUs), enzymes which are responsible for the cleavage of terminal sialic acids (SA) from sialoglycoconjugates, is not fully understood in RA. We investigated the impact of zanamivir, an inhibitor of the influenza virus neuraminidase, and mammalian NEU2/3 on clinical outcomes in experimental arthritides studies. The severity of arthritis was monitored and IgG titers were measured by ELISA. (2,6)-linked SA was determined on IgG by ELISA and on cell surfaces by flow cytometry. Zanamivir at a dose of 100 mg/kg (zana-100) significantly ameliorated collagen-induced arthritis (CIA), whereas zana-100 was ineffective in serum transfer-induced arthritis. Systemic zana-100 treatment reduced the number of splenic CD138+/TACI+ plasma cells and CD19+ B cells, which was associated with lower IgG levels and an increased sialylation status of IgG compared to controls. Our data reveal the contribution of NEU2/3 in CIA. Zanamivir down-modulated the T and B cell-dependent humoral immune response and induced an anti-inflammatory milieu by inhibiting sialic acid degradation. We suggest that neuraminidases might represent a promising therapeutic target for RA and possibly also for other antibody-mediated autoimmune diseases.
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Turgeon, Nathalie, Marie-Josée Toulouse, Jim Ho, Dongqing Li, and Caroline Duchaine. "Neuraminidase as an enzymatic marker for detecting airborne Influenza virus and other viruses." Canadian Journal of Microbiology 63, no. 2 (February 2017): 119–28. http://dx.doi.org/10.1139/cjm-2016-0450.
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Little information is available regarding the effectiveness of air samplers to collect viruses and regarding the effects of sampling processes on viral integrity. The neuraminidase enzyme is present on the surface of viruses that are of agricultural and medical importance. It has been demonstrated that viruses carrying this enzyme can be detected using commercial substrates without having to process the sample by methods such as RNA extraction. This project aims at evaluating the effects of 3 aerosol-sampling devices on the neuraminidase enzyme activity of airborne viruses. The purified neuraminidase enzymes from Clostridium perfringens, a strain of Influenza A (H1N1) virus, the FluMist influenza vaccine, and the Newcastle disease virus were used as models. The neuraminidase models were aerosolized in aerosol chambers and sampled with 3 different air samplers (SKC BioSampler, 3-piece cassettes with polycarbonate filters, and Coriolis μ) to assess the effect on neuraminidase enzyme activity. Our results demonstrated that Influenza virus and Newcastle disease virus neuraminidase enzymes are resistant to aerosolization and sampling with all air samplers tested. Moreover, we demonstrated that the enzymatic neuraminidase assay is as sensitive as RT–qPCR for detecting low concentrations of Influenza virus and Newcastle disease virus. Therefore, given the sensitivity of the assay and its compatibility with air sampling methods, viruses carrying the neuraminidase enzyme can be rapidly detected from air samples using neuraminidase activity assay without having to preprocess the samples.
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Souto, Ludmila Alves Dias, Alessandra Rejane Ericsson de Oliveira Xavier, and Mauro Aparecido de Sousa Xavier. "Amino Acid Substitutions Analysis of the Putative Epitopes of Neuraminidase Protein from Influenza A H1N1 Virus." Revista Unimontes Científica 22, no. 1 (January 26, 2021): 1–16. http://dx.doi.org/10.46551/ruc.v22n1a04.
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Objective: This study verified whether the neuraminidase protein of Influenza A H1N1 virus sequence has modified from 2009–2017 and its impact on the 2018 Brazilian vaccine. Method: The reference neuraminidase protein sequence from H1N1 Puerto Rico/1934 strain was subjected to three different methods of epitope prediction and the top five from each method were aligned using Clustal omega, resulting in eight putative epitopes. These epitopes were aligned to 7,438 neuraminidase sequences spanning from 2009–2017 and analyzed for specific amino acid substitutions and counted. The resultant neuraminidase protein was aligned against the 2015 and 2018 neuraminidase proteins, from Influenza A H1N1 virus subtypes, used for vaccine production. Result: Twenty-one main substitutions were detected, of which 16/21 (76.2%) substitutions points remained stable and 1/21 (4.8%) returned to the original amino acid residue in the viral population from 2009–2017. Additionally, 19% (4/21) substitutions occurred in Brazil and worldwide in this period, indicating that changes in the neuraminidase viral population profile is time-dependent rather than geographical. Conclusion: The neuraminidase protein containing these amino acid substitutions is more closely related to the neuraminidase protein from influenza A/Michigan/45/2015 than A/California/7/2009, supporting the replacement of this virus subtype in the Brazilian vaccine in 2018.
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Yee, H. F., J. N. Weiss, and G. A. Langer. "Neuraminidase selectively enhances transient Ca2+ current in cardiac myocytes." American Journal of Physiology-Cell Physiology 256, no. 6 (June 1, 1989): C1267—C1272. http://dx.doi.org/10.1152/ajpcell.1989.256.6.c1267.
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Sialic acid, an anionic sugar moiety found peripherally on membrane glycoconjugates, is specifically hydrolyzed from the cell surface by neuraminidase. Because neuraminidase has previously been demonstrated to augment myocardial cell calcium content, the effects of neuraminidase on Ca channel function were studied on voltage-clamped guinea pig ventricular myocytes. In 25-50% of cells, neuraminidase treatment (0.12 U/ml for 20 min) enhanced current through the transient (T) Ca channel by 304 +/- 35% without significantly altering the magnitude of the long-lasting (L) Ca channel current. Exposure to neuraminidase did not affect the voltage dependence of activation or inactivation, nor did it affect the selective inhibition of the T-channel current by amiloride or the L-channel current by nifedipine. After neuraminidase treatment, the T-channel current inactivated more rapidly (time constant decreasing from 8.9 +/- 0.9 to 7.7 +/- 0.6 ms), whereas there was no change in the rate of inactivation of the L-channel current. Neuraminidase treatment removed approximately 20% of the total cellular sialic acid. These results indicate that neuraminidase treatment selectively modulates the function of the T Ca channel in ventricular myocytes, possibly through removal of sarcolemmal sialic acid, suggesting that glycosylation of membrane macromolecules may influence membrane function.
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Anuwongcharoen, Nuttapat, Watshara Shoombuatong, Tanawut Tantimongcolwat, Virapong Prachayasittikul, and Chanin Nantasenamat. "Exploring the chemical space of influenza neuraminidase inhibitors." PeerJ 4 (April 19, 2016): e1958. http://dx.doi.org/10.7717/peerj.1958.
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The fight against the emergence of mutant influenza strains has led to the screening of an increasing number of compounds for inhibitory activity against influenza neuraminidase. This study explores the chemical space of neuraminidase inhibitors (NAIs), which provides an opportunity to obtain further molecular insights regarding the underlying basis of their bioactivity. In particular, a large set of 347 and 175 NAIs against influenza A and B, respectively, was compiled from the literature. Molecular and quantum chemical descriptors were obtained from low-energy conformational structures geometrically optimized at the PM6 level. The bioactivities of NAIs were classified as active or inactive according to their half maximum inhibitory concentration (IC50) value in which IC50< 1µM and ≥ 10µM were defined as active and inactive compounds, respectively. Interpretable decision rules were derived from a quantitative structure–activity relationship (QSAR) model established using a set of substructure descriptors via decision tree analysis. Univariate analysis, feature importance analysis from decision tree modeling and molecular scaffold analysis were performed on both data sets for discriminating important structural features amongst active and inactive NAIs. Good predictive performance was achieved as deduced from accuracy and Matthews correlation coefficient values in excess of 81% and 0.58, respectively, for both influenza A and B NAIs. Furthermore, molecular docking was employed to investigate the binding modes and their moiety preferences of active NAIs against both influenza A and B neuraminidases. Moreover, novel NAIs with robust binding fitness towards influenza A and B neuraminidase were generated via combinatorial library enumeration and their binding fitness was on par or better than FDA-approved drugs. The results from this study are anticipated to be beneficial for guiding the rational drug design of novel NAIs for treating influenza infections.
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Baricos, W. H., S. Cortez-Schwartz, and S. V. Shah. "Renal neuraminidase. Characterization in normal rat kidney and measurement in experimentally induced nephrotic syndrome." Biochemical Journal 239, no. 3 (November 1, 1986): 705–10. http://dx.doi.org/10.1042/bj2390705.
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Several lines of evidence suggest that increased neuraminidase activity may be responsible for the loss of glomerular N-acetylneuraminic acid (AcNeu) observed in various glomerular diseases. However, virtually no information is available on the activity of neuraminidase in glomeruli or the potential role of this enzyme in glomerular pathophysiology. Utilizing 2′-(4-methylumbelliferyl)-alpha-D-N-acetylneuraminic acid (4MU-AcNeu) as substrate, we defined optimal assay conditions and characterized neuraminidase activity in glomeruli and, for comparison, in other renal fractions and liver. Neuraminidase activity in glomeruli, cortex and tubules was maximal at pH 4.4. The Km for 4MU-AcNeu was estimated to be 195 microM for glomeruli and 226 microM for cortex. Glomerular neuraminidase was inhibited by AcNeu (90% at 25 mM) and high concentrations of Triton X-100 (26% at 0.5%), but unaffected by CaCl2, EDTA or N-ethylmaleimide (each 1 mM). Neuraminidase activity (nmol/h per mg of protein; mean +/- S.E.M.) in normal rat kidney was: cortex, 14.47 +/- 0.76; medulla, 7.85 +/- 0.64; papilla, 2.64 +/- 0.11; tubules, 13.79 +/- 0.70; glomeruli, 5.57 +/- 0.28. In comparison, neuraminidase activity in rat liver was 2.58 +/- 0.14. Puromycin aminonucleoside (PAN)-induced nephrotic syndrome is a model of glomerular disease in which the loss of glomerular AcNeu is well documented. In two separate studies, we observed no change in the specific activity of neuraminidase in either glomeruli or cortex isolated from rats treated with PAN (15 mg/100 g, intraperitoneally) and killed at either the onset or the peak of proteinuria. Results were similar whether neuraminidase activity was expressed per mg of protein or per microgram of DNA.
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Horga, Maria-Arantxa, G. Luca Gusella, Olga Greengard, Natalia Poltoratskaia, Matteo Porotto, and Anne Moscona. "Mechanism of Interference Mediated by Human Parainfluenza Virus Type 3 Infection." Journal of Virology 74, no. 24 (December 15, 2000): 11792–99. http://dx.doi.org/10.1128/jvi.74.24.11792-11799.2000.
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ABSTRACT Viral interference is characterized by the resistance of infected cells to infection by a challenge virus. Mechanisms of viral interference have not been characterized for human parainfluenza virus type 3 (HPF3), and the possible role of the neuraminidase (receptor-destroying) enzyme of the hemagglutinin-neuraminidase (HN) glycoprotein has not been assessed. To determine whether continual HN expression results in depletion of the viral receptors and thus prevents entry and cell fusion, we tested whether cells expressing wild-type HPF3 HN are resistant to viral infection. Stable expression of wild-type HN-green fluorescent protein (GFP) on cell membranes in different amounts allowed us to establish a correlation between the level of HN expression, the level of neuraminidase activity, and the level of protection from HPF3 infection. Cells with the highest levels of HN expression and neuraminidase activity on the cell surface were most resistant to infection by HPF3. To determine whether this resistance is attributable to the viral neuraminidase, we used a cloned variant HPF3 HN that has two amino acid alterations in HN leading to the loss of detectable neuraminidase activity. Cells expressing the neuraminidase-deficient variant HN-GFP were not protected from infection, despite expressing HN on their surface at levels even higher than the wild-type cell clones. Our results demonstrate that the HPF3 HN-mediated interference effect can be attributed to the presence of an active neuraminidase enzyme activity and provide the first definitive evidence that the mechanism for attachment interference by a paramyxovirus is attributable to the viral neuraminidase.
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Kati, Warren M., Debra Montgomery, Robert Carrick, Larisa Gubareva, Clarence Maring, Keith McDaniel, Kevin Steffy, et al. "In Vitro Characterization of A-315675, a Highly Potent Inhibitor of A and B Strain Influenza Virus Neuraminidases and Influenza Virus Replication." Antimicrobial Agents and Chemotherapy 46, no. 4 (April 2002): 1014–21. http://dx.doi.org/10.1128/aac.46.4.1014-1021.2002.
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ABSTRACT A-315675 is a novel, pyrrolidine-based compound that was evaluated in this study for its ability to inhibit A and B strain influenza virus neuraminidases in enzyme assays and influenza virus replication in cell culture. A-315675 effectively inhibited influenza A N1, N2, and N9 and B strain neuraminidases with inhibitor constant (Ki ) values between 0.024 and 0.31 nM. These values were comparable to or lower than the Ki values measured for oseltamivir carboxylate (GS4071), zanamivir, and BCX-1812, except for the N1 enzymes that were found to be the most sensitive to BCX-1812. The time-dependent inhibition of neuraminidase catalytic activity observed with A-315675 is likely due to its very low rate of dissociation from the active site of neuraminidase. The half times for dissociation of A-315675 from B/Memphis/3/89 and A/Tokyo/3/67 (H3N2) influenza virus neuraminidases of 10 to 12 h are significantly slower than the half times measured for oseltamivir carboxylate (33 to 60 min). A-315675 inhibited the replication of several laboratory strains of influenza virus in cell culture with potencies that were comparable or superior to those for oseltamivir carboxylate and BCX-1812, except for the A/H1N1 viruses that were found to be two- to fourfold more susceptible to BCX-1812. A-315675 and oseltamivir carboxylate exhibited comparable potencies against a panel of A/H1N1 and A/H3N2 influenza virus clinical isolates, but A-315675 was found to be significantly more potent than oseltamivir carboxylate against the B strain isolates. The favorable in vitro results relative to other clinically effective agents provide strong support for the further investigation of A-315675 as a potential therapy for influenza virus infections.
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Eneva, Rumyana, Stephan Engibarov, Tanya Strateva, Radoslav Abrashev, and Ignat Abrashev. "Biochemical studies on the production of neuraminidase by environmental isolates of Vibrio cholerae non-O1 from Bulgaria." Canadian Journal of Microbiology 57, no. 7 (July 2011): 606–10. http://dx.doi.org/10.1139/w11-042.
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Neuraminidase is a key factor in the infectious process of many viruses and pathogenic bacteria. The neuraminidase enzyme secreted by the etiological agent of cholera — Vibrio cholerae О1 — is well studied in contrast with the one produced by non-O1/non-O139 V. cholerae. Environmental non-O1/non-O139 V. cholerae isolates from Bulgaria were screened for production of neuraminidase. The presence of the neuraminidase gene nanH was detected in 18.5% of the strains. Тhe strain showing highest activity (30 U/mL), V. cholerae non-O1/13, was used to investigate the enzyme production in several media and at different aeration conditions. The highest production of extracellular neuraminidase was observed under microaerophilic conditions, which is possibly related to its role in the infection of intestine epithelium, where the oxygen content is low. On the other hand, this is another advantage of the microbe in such microaerophilic environments as sediments and lake mud. The highest production of intracellular neuraminidase was observed at anaerobic conditions. The ratio of extracellular to intracellular neuraminidase production in V. cholerae was investigated. The temperature optimum of the enzyme was determined to be 50 °C and the pH optimum to be 5.6–5.8.
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Cabezas Fernández del Campo, José Antonio. "Neuraminidase / sialidase from influenza virus: its characteristics, nomenclature, measuring of activity, kinetics, inhibitors as therapeutic agents." Anales de la Real Academia Nacional de Farmacia 88, no. 88(05) (December 31, 2022): 409–13. http://dx.doi.org/10.53519/analesranf.2022.88.05.07.
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The main characteristics of neuraminidase / sialidase from Influenza Virus and its peculiar nomenclature are described, as well as two new, sensitive and simple procedures (fluorometric and by luminiscence) for measuring neuraminidase activity, which have been used at the Department of Biochemistry and Molecular Biology of the University of Salamanca (Prof. J. A. Cabezas). The kinetics of neuraminidase of three A and three B Influenza Virus Strains, and the result of the comparison of biological and physical properties of human and animal origin (pig and duck) Virus Strains, belonging to the same subtype A(H1N1), are described. Finally, the advantages and risks for the use as therapeutic agents against Influenza of the Influenza Virus neuraminidase inhibitors Zanamivir, Oseltamivir and Peramivir are discussed. Keywords: neuraminidase / sialidase; influenza virus; inhibitors
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Porotto, Matteo, Matthew Murrell, Olga Greengard, Lynne Doctor, and Anne Moscona. "Influence of the Human Parainfluenza Virus 3 Attachment Protein's Neuraminidase Activity on Its Capacity To Activate the Fusion Protein." Journal of Virology 79, no. 4 (February 15, 2005): 2383–92. http://dx.doi.org/10.1128/jvi.79.4.2383-2392.2005.
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ABSTRACT In order to examine functions of the hemagglutinin-neuraminidase (HN) protein that quantitatively influence fusion promotion, human parainfluenza virus 3 (HPIV3) variants with alterations in HN were studied. The variant HNs have mutations that affect either receptor binding avidity, neuraminidase activity, or fusion protein (F) activation. Neuraminidase activity was regulated by manipulation of temperature and pH. F activation was assessed by quantitating the irreversible binding of target erythrocytes (RBC) to HN/F-coexpressing cells in the presence of 4-GU-DANA (zanamivir) to release target cells bound only by HN-receptor interactions; the remaining, irreversibly bound target cells are retained via the fusion protein. In cells coexpressing wild-type (wt) or variant HNs with wt F, the fusion promotion capacity of HN was distinguished from target cell binding by measuring changes with time in the amounts of target RBC that were (i) reversibly bound by HN-receptor interaction (released only upon the addition of 4-GU-DANA), (ii) released by HN′s neuraminidase, and (iii) irreversibly bound by F-insertion or fusion (F triggered). For wt HN, lowering the pH (to approach the optimum for HPIV3 neuraminidase) decreased F triggering via release of HN from its receptor. An HN variant with increased receptor binding avidity had F-triggering efficiency like that of wt HN at pH 8.0, but this efficiency was not decreased by lowering the pH to 5.7, which suggested that the variant HN′s higher receptor binding activity counterbalanced the receptor dissociation promoted by increased neuraminidase activity. To dissect the specific contribution of neuraminidase to triggering, two variant HNs that are triggering-defective due to a mutation in the HN stalk were evaluated. One of these variants has, in addition, a mutation in the globular head that renders it neuraminidase dead, while the HN with the stalk mutation alone has 30% of wt neuraminidase. While the variant without neuraminidase activity triggered F effectively at 37°C irrespective of pH, the variant possessing effective neuraminidase activity completely failed to activate F at pH 5.7 and was capable of only minimal triggering activity even at pH 8.0. These results demonstrate that neuraminidase activity impacts the extent of HPIV3-mediated fusion by releasing HN from contact with receptor. Any particular HN′s competence to promote F-mediated fusion depends on the balance between its inherent F-triggering efficacy and its receptor-attachment regulatory functions (binding and receptor cleavage).
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Yang, Ping, Anju Bansal, Chongguang Liu, and Gillian M. Air. "Hemagglutinin Specificity and Neuraminidase Coding Capacity of Neuraminidase-Deficient Influenza Viruses." Virology 229, no. 1 (March 1997): 155–65. http://dx.doi.org/10.1006/viro.1996.8421.
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Abrashev, Ignat, and Petya Orozova. "Erysipelothrix rhusiopathiae Neuraminidase and its Role in Pathogenicity." Zeitschrift für Naturforschung C 61, no. 5-6 (June 1, 2006): 434–38. http://dx.doi.org/10.1515/znc-2006-5-621.
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The role of the enzyme neuraminidase in pathogenicity of the bacillus Erysipelothrix rhusiopathiae was studied. Different substances with low and high molecular weight were tested as inducers of E. rhusiopathiae neuraminidase biosynthesis. It was found that macromolecular complexes induce the secretion of the enzyme. Kм values for different substrates showed that the affinity of the E. rhusiopathiae neuraminidase increases in parallel with the enlargement of the molecular weight of glycoproteins. Results from the rabbits skin test confirmed the role of E. rhusiopathiae neuraminidase as a factor of pathogenicity with spreading functions.
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Hooper, Kathryn A., James E. Crowe, and Jesse D. Bloom. "Influenza Viruses with Receptor-Binding N1 Neuraminidases Occur Sporadically in Several Lineages and Show No Attenuation in Cell Culture or Mice." Journal of Virology 89, no. 7 (January 21, 2015): 3737–45. http://dx.doi.org/10.1128/jvi.00012-15.
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ABSTRACTIn nearly all characterized influenza viruses, hemagglutinin (HA) is the receptor-binding protein while neuraminidase (NA) is a receptor-cleaving protein that aids in viral release. However, in recent years, several groups have described point mutations that confer receptor-binding activity on NA, albeit in laboratory rather than natural settings. One of these mutations, D151G, appears to arise in the NA of recent human H3N2 viruses upon passage in tissue culture. We inadvertently isolated the second of these mutations, G147R, in the NA of the lab-adapted A/WSN/33 (H1N1) strain while we were passaging a heavily engineered virus in the lab. G147R also occurs at low frequencies in the reported sequences of viruses from three different lineages: human 2009 pandemic H1N1 (pdmH1N1), human seasonal H1N1, and chicken H5N1. Here we reconstructed a representative G147R NA from each of these lineages and found that all of the proteins have acquired the ability to bind an unknown cellular receptor while retaining substantial sialidase activity. We then reconstructed a virus with the HA and NA of a reported G147R pdmH1N1 variant and found no attenuation of viral replication in cell culture or change in pathogenesis in mice. Furthermore, the G147R virus had modestly enhanced resistance to neutralization by the Fab of an antibody against the receptor-binding pocket of HA, although it remained completely sensitive to the full-length IgG. Overall, our results suggest that circulating N1 viruses occasionally may acquire the G147R NA receptor-binding mutation without impairment of replicative capacity.IMPORTANCEInfluenza viruses have two main proteins on their surface: one (hemagglutinin) binds incoming viruses to cells, while the other (neuraminidase) helps release newly formed viruses from these same cells. Here we characterize unusual mutant neuraminidases that have acquired the ability to bind to cells. We show that the mutation that allows neuraminidase to bind cells has no apparent adverse effect on viral replication but does make the virus modestly more resistant to a fragment of an antibody that blocks the normal hemagglutinin-mediated mode of viral attachment. Our results suggest that viruses with receptor-binding neuraminidases may occur at low levels in circulating influenza virus lineages.
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Hurt, Aeron C., Jessica K. Holien, and Ian G. Barr. "In Vitro Generation of Neuraminidase Inhibitor Resistance in A(H5N1) Influenza Viruses." Antimicrobial Agents and Chemotherapy 53, no. 10 (August 3, 2009): 4433–40. http://dx.doi.org/10.1128/aac.00334-09.
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ABSTRACT To identify mutations that can arise in highly pathogenic A(H5N1) viruses under neuraminidase inhibitor selective pressure, two antigenically different strains were serially passaged with increasing levels of either oseltamivir or zanamivir. Under oseltamivir pressure, both A(H5N1) viruses developed a H274Y neuraminidase mutation, although in one strain the mutation occurred in combination with an I222M neuraminidase mutation. The H274Y neuraminidase mutation reduced oseltamivir susceptibility significantly (900- to 2,500-fold compared to the wild type). However the dual H274Y/I222M neuraminidase mutation had an even greater impact on resistance, with oseltamivir susceptibility reduced significantly further (8,000-fold compared to the wild type). A similar affect on oseltamivir susceptibility was observed when the dual H274Y/I222M mutations were introduced, by reverse genetics, into a recombinant seasonal human A(H1N1) virus and also when an alternative I222 substitution (I222V) was generated in combination with H274Y in A(H5N1) and A(H1N1) viruses. These viruses remained fully susceptible to zanamivir but demonstrated reduced susceptibility to peramivir. Following passage of the A(H5N1) viruses in the presence of zanamivir, the strains developed a D198G neuraminidase mutation, which reduced susceptibility to both zanamivir and oseltamivir, and also an E119G neuraminidase mutation, which demonstrated significantly reduced zanamivir susceptibility (1,400-fold compared to the wild type). Mutations in hemagglutinin residues implicated in receptor binding were also detected in many of the resistant strains. This study identified the mutations that can arise in A(H5N1) under either oseltamivir or zanamivir selective pressure and the potential for dual neuraminidase mutations to result in dramatically reduced drug susceptibility.
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Richard, Mathilde, Claire Deléage, Mendy Barthélémy, Yi Pu Lin, Alan Hay, Bruno Lina, and Olivier Ferraris. "Impact of influenza A virus neuraminidase mutations on the stability, activity, and sensibility of the neuraminidase to neuraminidase inhibitors." Journal of Clinical Virology 41, no. 1 (January 2008): 20–24. http://dx.doi.org/10.1016/j.jcv.2007.10.021.
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Mikurova, A. V., and V. S. Skvortsov. "Creation of a generalized model prediction of inhibition of neuraminidase of influenza virus of various strains." Biomeditsinskaya Khimiya 64, no. 3 (2018): 247–52. http://dx.doi.org/10.18097/pbmc20186403247.
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Preliminary results of construction of overall model for prediction of IC50 value of ligands of influenza virus neuraminidase of any strain are presented. We used MM-PBSA (MM-GBSA) energy terms calculated for the complexes obtained after modeling of 30 variants of neuraminidase structures, subsequent docking and simulation of molecular dynamics as independent variables in prediction equations. The structures of known neuraminidase-inhibiting drugs (oseltamivir, zanamivir and peramivir) and a neuraminidase substrate (MUNANA) were used as ligands. The correlation equation based on calculated energetic parameters of inhibitor complexes with neuraminidase did not result in the prediction of IC50 with acceptable parameters (R2£0.3). However, if information about binding energy of the substrate used for neuraminidase assay (and IC50 detection) is included the resulting IC50 prediction equations become significant (R2³0.55). It is concluded that models based on IC50 values as a predictable variable and combining information about binding of different ligands to different variants of the target proteins must take into account the binding properties of the substrate (used for IC50 determination). The predictive power of such models depends critically on the quality of the modeling of the ligand-protein complexes.
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Gallagher, RE, DA Giangiulio, CS Chang, CJ Glover, and RL Felsted. "Hyposialylation of differentiation-inducer-resistant HL-60 cells." Blood 68, no. 6 (December 1, 1986): 1402–6. http://dx.doi.org/10.1182/blood.v68.6.1402.1402.
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Abstract The total sialic acid concent of retinoic acid (RA)-resistant or 6- thioguanine (6TG)-resistant HL-60 cells was more than tenfold lower and of dimethylsulfoxide (DMSO)-resistant HL-60 cells was approximately twofold lower than that of parental, wild-type (wt) HL-60 cells. Neuraminidase-inaccessible, ie residual cell-associated sialic acid after neuraminidase treatment, was four- to twelvefold lower in the three differentiation-inducer-resistant sublines than in the parent line. Neuraminidase treatment of 125I-labeled surface membrane glycoproteins (SMGs) from wt HL-60 cells converted the two-dimensional gel electrophoretic pattern to one having features in common with RA- and 6TG-resistant cells. However, neuraminidase treatment did not alter the sensitivity of wt HL-60 cells to differentiation induction by RA, hypoxanthine (purine base), or DMSO. These results indicate that differences in peripheral, neuraminidase-accessible sialic acids are important determinants of the gel electrophoretic mobility of the SMGs of the HL-60 line and sublines but are not likely related to the differentiation-resistance mechanism. Further studies are required to determine if hyposialylation of cryptic, neuraminidase-inaccessible sites has functional significance.
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Gallagher, RE, DA Giangiulio, CS Chang, CJ Glover, and RL Felsted. "Hyposialylation of differentiation-inducer-resistant HL-60 cells." Blood 68, no. 6 (December 1, 1986): 1402–6. http://dx.doi.org/10.1182/blood.v68.6.1402.bloodjournal6861402.
Full textAbstract:
The total sialic acid concent of retinoic acid (RA)-resistant or 6- thioguanine (6TG)-resistant HL-60 cells was more than tenfold lower and of dimethylsulfoxide (DMSO)-resistant HL-60 cells was approximately twofold lower than that of parental, wild-type (wt) HL-60 cells. Neuraminidase-inaccessible, ie residual cell-associated sialic acid after neuraminidase treatment, was four- to twelvefold lower in the three differentiation-inducer-resistant sublines than in the parent line. Neuraminidase treatment of 125I-labeled surface membrane glycoproteins (SMGs) from wt HL-60 cells converted the two-dimensional gel electrophoretic pattern to one having features in common with RA- and 6TG-resistant cells. However, neuraminidase treatment did not alter the sensitivity of wt HL-60 cells to differentiation induction by RA, hypoxanthine (purine base), or DMSO. These results indicate that differences in peripheral, neuraminidase-accessible sialic acids are important determinants of the gel electrophoretic mobility of the SMGs of the HL-60 line and sublines but are not likely related to the differentiation-resistance mechanism. Further studies are required to determine if hyposialylation of cryptic, neuraminidase-inaccessible sites has functional significance.
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Henry, Ronnie, and Frederick A. Murphy. "Etymologia: Hemagglutinin and Neuraminidase." Emerging Infectious Diseases 24, no. 10 (October 2018): 1849. http://dx.doi.org/10.3201/eid2410.et2410.
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