Neuraminidase activity

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... 

Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, Oxford JS, Hayden FG, Roberts NA (2002) The H274Y mutation in the influenza A/HINI neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res 55 307-317... 

Control experiments verified that the neuraminidase active site was responsible for controlling DCL evolution. First, substitution of neuraminidase with bovine serum albumin as the target produced no amplification at all. Second, reconstituting the DCL in the presence of excess zanamivir, a commercially available potent inhibitor of neuraminidase, likewise gave results identical to the blank DCL in the absence of any target. 

Oseltamivir (1) is a prodrug of GS-4071 (7, Fig. 7.2). It is also a potent competitive inhibitor of viral neuraminidase glycoprotein for both influenza A and B types. Similar to zanamivir (2), oseltamivir (1) is also the fmit of SBDD in the sense that the protein structure directed the design of the ligand (sialic acid) and the protein-bound ligand conformation is close to the designed stmcture. In particular, the neuraminidase active site contains several... 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

All the nearest-neighbor interactions between sialic acid or Neu5Ac2en and the protein are with totally conserved amino acids. Thus an inhibitor designed to bind only to the conserved active-site residues of neuraminidase would inhibit neuraminidase activity across all strains of influenza. This would enable the development of an antiviral drug that would affect the spread of viral replication potentially in three ways, i.e., transport through the protective mucosal layer, desialyation of freshly synthesized viral glycoproteins, and elution of progeny virions from infected cells. 

The 4-guanidino analog shows potent inhibition of neuraminidase activity in all known wild strains of influenza. Furthermore it is very specific to in-... 

Laver WG. The structure of influenza virus 3. Disruption of the virus particle and separation of neuraminidase activity. Virology 1963 20 251-262. 

P. Meindl, G. Bodo, P. Palese, J. Schulman, and H. Tuppy, Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-jV-acetylneuraminic acid, Virology, 58 (1974) 457 463. 

Figure 6. The effect of neuraminidase on the EAP phenotype patterns obtained during electrophoresis for 4 hr at 0°C. Samples 1 4 contained no neuraminidase. Samples 5-9 contained 10 units of neuraminidase activity per ml. All samples were incubated at 25°C. The photograph taken at 114 hr was exposed for 6 min to enhance EAP activity observed in samples 1 4. A 2-min exposure was used for photographs taken at the other times. The only EAP activity observed after incubation with neuraminidase for 114 hr was the c isozyme band of sample 5 (EAP phenotype AC). The c isozyme is the most stable of the four EAP isozymes (5).

These efforts have culminated in the hve-membered carbocyclic compound peramivir 41, which is an orally available influenza neuraminidase inhibitor, obtained by rational design [90]. In a comprehensive study, 41 has been shown to possess neuraminidase activity comparable with both zanamivir 28 and oseltamivir 35 against a number of influenza strains. Furthermore, 41 was found to be very selective for influenza neuraminidase over mammalian, bacterial or other viral neuraminidases. Peramivir 41 is currently undergoing clinical evaluation as an oral treatment for influenza in humans [90b]. 

Most cultures from Collection IBSO produce lyases L-ornithine, L-arginine, and L-lysine decarboxylases. Neuraminidase (sialidase, or mucopolysaccharide - N-acetylneuraminilhydrolase) is the enzyme of the hydrolase group. As is usual neuraminidase activity is a property of pathogenic organisms. We found for the first time that luminous bacterial cultures of the species V. harveyi possess low neuraminidase activity. It may be probably one of the factors contributing to contamination of marine animals by luminous bacteria. 

Sialidases such as the influenza neuraminidase are retaining enzymes that catalyze the hydrolysis of a-D-A -acetylneuraminic acids from oligosaccharides or glycolipids and glycoproteins. Inhibitors of these enzymes are of great interest since it has been shown that neuraminidase activity can correlate with virulence. ... 

Influenza neuraminidase cleaves terminal sialic acid residues and destroys the receptors recognized by viral hemagglutinin, which are present on the cell surface, in progeny virions, and in respiratory secretions. This enzymatic action is essential for release of virus from infected cells. Interaction of oseltamivir carboxylate with the neuraminidase causes a conformational change within the enzyme s active site and inhibits its activity. Inhibition of neuraminidase activity leads to viral aggregation at the cell surface and reduced virus spread within the respiratory tract. 

The last example of a modification of RIS as a result of a mutation is that of liver neuraminidase in the SM/J mouse (Yan et al., unpublished work). The SM/J mouse is a mutant with a severe 4-methylumbelliferyl-a-D-V-acetylneuraminate neuraminidase deficiency in the liver (Potier et al., 1979). The residual neuraminidase activity in SM/J mouse liver is due to a thermostable component that differs in isoelectric point and RIS... 

Trypanosoma cruzi expresses a neuraminidase activity which is developmentally regulated. Enzyme aetivity is maximal in infective trypomastigotes, 10 to 560 times less in epimastigotes, and is absent in amastigotes. The neuraminidase, of an apparent moleeular mass of 160-200 kDa, is located on the outer membrane and is released by a stage-specifie phospholipase C. Of interest is the presence of sequences similar to low-density lipoprotein receptor and to the type III module of fibronectin (14). 

A striking observation was that inhibition of the neuraminidase activity with either antibodies or high- and low-density lipoproteins enhances infectivity of T. cruzi in... 

CHEMISTRY AND ANTIVIRAL ACTIVITY Zanamivir (4-guanidino-2,4-dideoxy-2, 3-dehydro-/V-acetyl neuraminic acid) is a siaMc acid analog that potently and specifically inhibits the neuraminidases of influenza A and B viruses. Depending on the strain, zanamivir competitively inhibits influenza neuraminidase activity but affects neuraminidases from other pathogens and mammalian sources only at much higher concentrations. Zanamivir inhibits in vitro replication of influenza A and B viruses, including amantadine- and rimantadine-resistant strains and several oseltamivir-resistant variants. 

S. Sehenkman, L. Pontes de Carvalho, and V. Nussenzweig, Trypanosoma cruzi trans-siahdase and neuraminidase activities can be mediated by the same enzymes, J. Exp. Med., 175 (1992) 567-575. 

These allowed distinction between types of neuraminidase activities. Results confirmed, inter alia, the hypothesis of a specific defect of a-(2 -> 6)-neuramini-dase in the case of a sialidosis B. 

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