Neuraminidase of influenza virus

Varghese IN, Colman PM (1991) Three-dimensional structure of the neuraminidase of influenza virus A/Tokyo/3/67 at 2.2 A resolution. 1 Mol Biol 221 473 86 Varghese IN, Laver WG, Colman PM (1983) Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature 303 35 0 Varghese IN, McKimm-Breschkin IL, Caldwell IB, Kortt AA, Colman PM (1992) The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins 14 327-332... 

Sialidases are enzymes that catalyze the removal of terminal sialic acids from sialosides (56, 57). Human sialidases play pivotal roles in sialic acid metabolism (58). They relate to a number of disease states such as sialidosis (59-62) and cancer (63-65). Bacterial and viral play significant roles in the pathogenesis and pathology of bacterial and viral infections (66, 67). Viral sialidases such as neuraminidases of influenza virus catalyze the removal of sialic acid from the surface of infected host cells to release the newly formed progeny virus (68). 

Varghese JN, Webster RG, Laver WG, Colman PM. Structure of an escape mutant of glycoprotein N2 neuraminidase of influenza virus A/Tokyo/3/67 at 3 A. J Mol Biol 1988 200 201-203. 

Air GM, Laver WG. (1989) The neuraminidase of influenza virus. Prot. Struct. Funct. Genet. 6, 341-356. 

Haussman, J., Kretzshcmear, E., Garten, W., and Klenk, H. D., 1995, N1 neuraminidase of influenza virus AIFPVlRostock 134 has hem-adsorbing activity, J. Gen. Virol, in press. 

Wilson, V. W., and Rafelson, M. E., Jr., 1967, Studies on the neuraminidases of influenza viruses. III. Stimulation of activity by bivalent cations, Biochim. Biophys. Acta 140 160-166. 

Rafelson, M., Wilson, and Schneir, M., 1962, The neuraminidases of influenza virus. Presbyterian St. Luke Hosp. Med. Bull. 1 34-39. 

Zhumatov, Kh. Vr., Isaeva, E. S., Chuvakova, Z. K., and Stetsenko, O. G., 1972, Investigation of electrophoretic mobility and immunospecificity of the neuraminidases of influenza virus and host ceUs, Byull. Eksp. Biol. Med. 73 68-71. 

Jedrzejas, M. J., Singh, S. Brouillette, W. J. Air, G. M. Luo, M. A. 1995. Strategy for theoretical binding constant, Ki calculation for neuraminidase aromatic inhibitors, designed on the basis of the active site structure of influenza virus neuraminidase. Proteins Struct. Funct. Genet. 23 (1995) 264-277... 

A second example of up-and-down p sheets is the protein neuraminidase from influenza virus. Here the packing of the sheets is different from that in RBP. They do not form a simple barrel but instead six small sheets, each with four P strands, which are arranged like the blades of a six-bladed propeller. Loop regions between the p strands form the active site in the middle of one side of the propeller. Other similar structures are known with different numbers of the same motif arranged like propellers with different numbers of blades such as the G-proteins discussed in Chapter 13. 

Figure S.6 Schematic and topological diagrams of the folding motif in neuraminidase from influenza virus The motif is built up from four antiparallel P strands joined by hairpin loops, an up-and-down open P sheet.

We have already discussed one envelope protein of influenza virus, neuraminidase, as an example of an up-and-down antiparallel p motif. In the second envelope protein, hemagglutinin, one domain of the polypeptide chain is folded into a jelly roll motif. We shall now look at some other features of hemagglutinin that are important for its biological function. 

Another important specific enzymatic target is neuraminidase, which is found on the envelope of influenza viruses (see chapter by von Itzstein and Thomson, this... 

An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter. 

Colman PM, Ward CW (1985) Structure and diversity of influenza virus neuraminidase. Curr Top Microbiol Immunol 114 177-255... 

Gubareva LV (2004) Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors, Virus Res 103 199-203... 

Gubareva LV, Robinson MJ, Bethell RC, Webster RG (1997) Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en, J Virol 71 3385-3390... 

Matrosovich M, Klenk H-D (2003) Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Rev Med Virol 13 85-97 Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk H-D (2004) Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 78 12665-12667... 

McKimm-Breschkin JL (2000) Resistance of influenza viruses to neuraminidase inhibitors - a review. Antiviral Res 47 1-17... 

Ryan DM, Ticehurst J, Dempsey M, Penn CR (1994) Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-iV-acetylneuraminic add) is consistent with extracellular actiivity of viral neuraminidase (sialidase), Antimicrob Agents Chemother 10 2270-2275... 

Smith BJ, McKimm-Breshkin JL, McDonald M, Fernley RT, Varghese JN, Colman PM (2002) Structural studies of the resistance of influenza virus neuraminidase to inhibitors. J Med Chem... 

Watson KG, Cameron R, Fenton RJ, Gower D, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell D, MacDonald SJ, Mason AM, Nguyen V, Tucker SP, Wu WY (2004) Highly potent and long-acting trimeric and tetrameiic inhibitors of influenza virus neuraminidase. Bioorg Med Chem Lett 14 1589-1592... 

Yamashita M, Ohno A, TomozawaT, Yoshida S (2003) R-118958, a unique anti-influenza agenf. I. A prodrug form of R-125489, a novel inhibitor of influenza virus neuraminidase. In 43rd in-tersdence conference on antimicrobial agents and chemotherapy, Chicago, USA, Sept 14-17, Poster F-1829... 

Sivasubramanian, N. and Nayak, D. P. Mutational analysis of the signal-anchor domain of influenza virus neuraminidase. Proc. Natl. Acad. Sci. U.S.A. 84 1-5,1987. 

Neuraminidases are enzymes present in viruses, bacteria, and parasites. They are implicated in serious diseases such as cholera, meningitis and pneumonia. Neuraminidase from influenza virus aids the transmission of the virus between cells and maintains viral infectivity. In different strains of influenza several amino acids are conserved, especially in the active site, giving rise to hopes of finding a single inhibitor (and so a drug) for all the neuraminidase enzymes from influenza strains. The crucial question is whether a covalent bond is formed between the enzyme and the reaction intermediate. 

Immunopotentiating reconstituted influenza virosomes (IRTV) are spherical 150-nm sized particles consisting of a phospholipid bilayer in which influenza virus A/Singapore strain-derived hemagglutinin (HA) and neuraminidase (NA) are intercalated. As such, they resemble and mimic the influenza virus envelope. The difference from conventional liposome formulations lies in the inclusion of the viral envelope proteins HA and NA as well as viral phospholipids. Especially, the inclusion of influenza virus HA provides IRIV with delivery and immimogenic capacities. IRTV are licensed for human use as adjuvant in hepatitis A vaccination and as influenza subunit vaccine (1). 

In order to exclusively measure binding of ligands to HA and to prevent binding to neuraminidase, a neuraminidase inhibitor Neu5Ac2en (Scheme 1) is added at high concentrations (10-20 mM) in all cases. Neuraminidase is also present on the surface of Influenza viruses and shares binding specificities with HA. 

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