Influenza viruses, potentiation

Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. ... 

Analysis of Potential Binding Interactions within the Influenza Virus Sialidase Active Site... 

Fig. 7 The influenza virus A sialidase active site showing the five potential inhibitor binding subsites (with S5 containing the hydrophobic pocket formed by reorientation of the Glu276 side-chain), with oseltamivir carboxylate 18 placed in the active site...

An interesting feature of the influenza virus sialidase active site that offers the potential for developing inhibitors specific for N1 sialidases, including avian influenza A/H5N1 virus sialidase, has recently been revealed by X-ray crystallography. The... 

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

What are the characteristics that make the influenza virus, for example, avian influenza, a potential pandemic agent ... 

The discovery of Zanamivir as a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis and structure-activity relationship studies of Neu5Ac2en-based compounds as potential sialidase inhibitors. Exploration of these SAR studies were undertaken to optimize inhibitory activity and to improve the physicochemical properties of the sialic acid-based influenza virus sialidase inhibitor. A few in vitro assays are commonly employed to measure the effectiveness of influenza virus sialidase inhibitors. The first involves a fluorometric assay that measures release of a synthetic fluorophore following its cleavage from Neu5Ac by sialidase. Dye-uptake assay, such as the Neutral Red uptake assay, measures the uptake of a vital stain, Neutral Red in cell culture. The process requires intact membranes and active metabolism in the cell, and is expressed as percent protective rate against virus infection. The plaque-reduction assay is used to measure sialidase inhibition indirectly in cell culture, and provides some measure of the inhibitor s effect on the viability of the influenza virus. In vitro and in vivo systems for analysis of inhibitors of influenza virus enzymes have been reviewed.71... 

The worldwide spread of H5N1 avian influenza virus has raised the concern of its potential to emerge as a human-adapted virus. Three decades of intense research have yielded only two NA inhibitors, Relenza and Tamiflu , that... 

P.-A. Driguez, B. Barrere, G. Quash, and A. Doutheau, Synthesis of transition-state analogues as potential inhibitors of sialidase from influenza virus, Carbohydr. Res., 262 (1994) 297-310. 

Modeling studies carried out by Mark von Itzstein s group [ 137] on the 150-loop open structures of group 1 sialidase Nl revealed the possibility to access the predominantly hydrophobic 150-cavity by an appropriate substitution at C3 of 11. As shown in Figure 17.18, an opportune substitution at C3 of 11 would be accommodated in the 150-cavity in the more open form of influenza virus sialidase of group 1 and could also potentially bind to the active site with minimal distortion of the normal binding mode of 11. 

A number of C-4-substituted 2,3-didehydro derivatives show significant inhibition of influenza A and B virus sialidase. The C-4 amino derivative (163) was originally targeted as a potential inhibitor of influenza virus sialidase based on molecular modelling studies of the X-ray crystal structure of influenza A virus sialidase [189-191]. 

Reports on the anti-influenza virus effects of extracts from marine algae from all over the world have been found in the literature [115]. These results show that the blue-green algae (cyanobacterium) are able to produce compounds with anti-influenza activity that may be of potential clinical interest. For example, aqueous and methanolic extracts of cultured cyanobacteria of several genera. Microcystis, Nodularia, Oscillatoria, Scytonema, Lyngbya and Calothrix were evaluated for their in vitro antiviral activity against the influenza A virus in Madin Darby kidney cells [116,117]. The further analysis of methanolic extracts of cultured strains of genus Microcystis revealed a remarkable antiviral... 

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