Influenza vims

RNA-dependent RNA polymerase influenza vims, patamyxovims, vesiculovims... 

Both amantadiae and rknantadiae have been found to reduce the duration of influenza A-iaduced fever and malaise, and to lessen viral shedding. Prophylactic treatment has been recommended for high risk patients (95). It has been suggested that, ia the presence of amantadine, the influenza vims attaches normally to cells, but once iaside the ceU the vims fails to initiate repHcation. Thus amantadine appears to inhibit the initiation of transcription at an early stage between uncoating and viral-specific RNA synthesis (96). 

Figure S.21 The hemaggiutinin moiecuie is formed from three subunits. Each of these subunits Is anchored In the membrane of the influenza vims. The globular heads contain the receptor sites that bind to sialic acid residues on the surface of eukaryotic cells. A major part of the subunit interface is formed by the three long intertwining helices, one from each subunit. (Adapted from I. Wilson et al.. Nature 289 366-373, 1981.)...

The second protein in the membrane of influenza vims, neuraminidase, does not belong to any of these three groups of barrel structures. Instead, it forms a propeller-like structure of 24 p strands, arranged in six similar motifs that form the six blades of the propeller. Each motif is a p sheet of 4 up-and-down-connected p strands. The enzyme active site is formed by loop regions on one side of the propeller. 

A large and rapidly growing number of clinical trials (phase I and phase II) evaluating the potential of DNA vaccines to treat and prevent a variety of human diseases are currently being performed ( http // clinicaltrials.gov) however, there is yet no licensed DNA vaccine product available for use in humans. The clinical trials include the treatment of various types of cancers (e.g., melanoma, breast, renal, lymphoma, prostate, and pancreas) and also the prevention and therapy of infectious diseases (e.g., HIV/ABDS, malaria, Hepatitis B vims, Influenza vims, and Dengue vims). So far, no principally adverse effects have been reported from these trials. The main challenge for the development of DNA vaccines for use in humans is to improve the rather weak potency. DNA vaccines are already commercially available for veterinary medicine for prevention of West Nile Vims infections in horses and Infectious Hematopoetic Necrosis Vims in Salmon. 

Neuraminidase inhibitors are the major class of drugs to treat or to prevent the infection with influenza viruses. Currently, two neuraminidase inhibitors are available, zanamivir and oseltamivir, which block the release of new influenza vims from infected host cells and thereby stop the spread of infection. The enzyme neuraminidase is a surface glycoprotein present on all influenza viruses. There are nine influenza neuraminidase sub-types known of which subtypes N1 and N2 appear to be the most important ones. Neuraminidase inhibitors are effective against all neuraminidase subtypes. The activity of the neuraminidase is required for the newly... 

F%.2 A view of the influenza vims sialidase (NA) monomer with a-Neu5Ac 3a bound in the active site... 

In the following sections, an overview of some of the key developments in the discovery of potent influenza vims sialidase inhibitors is provided. In the first instance, the discovery of the influenza vims sialidase inhibitors that have become the current first-hne-of-defence anti-influenza dmgs will be described, followed by a description of some of the other important sialidase inhibitor developments to date. 

Palese P, Compans RW (1976) Inhibition of influenza vims replication in tissue culture by 2-deoxy-2,3-dehydro-A-trifluoroacetylneuraminic acid (EANA) mechanism of action, J Gen Virol 33 159-163... 

Human viruses will cause disease in other animals. Some are capable of infecting only a few closely related primate species, others will infect a wide range of mammals. Under the conditions of natural infection vimses generally exhibit a considerable degree of tissue specificity. The influenza vims, for example, replicates only in the cells lining the upper respiratory tract. 

Fig. 3.8 Diagrammatic representation of the production and release of influenza vims particles liom an infected cell.

Streptococcus pneumonia, Haemophilus influenzae, and influenza vims... 

In general, virus receptors carry out normal functions in the cell. For example, in bacteria some phage receptors are pili or flagella, others are cell-envelope components, and others are transport binding proteins. The receptor for influenza vims is a glycoprotein found on red blood cells and on cells of the mucous membrane of susceptible animals, whereas the receptor site of poliovirus is a lipoprotein. However, many animal and plant viruses do not have specific attachment sites at all and the vims enters passively as a result of phagocytosis or some other endocytotic process. 

Li J et al. Typing and subtyping influenza vims using DNA microarrays and... 

Listeria monocytogenes Streptococcus pneumoniae Plasmodium yoelli Influenza Vims Cytomegalovims Trichinella spiralis PYB6 Sarcoma B16F10 Melanoma... 

Lawrence, B.R and Vorderstrasse, B., A kinetic study of the recall response to influenza vims infection in mice exposed to the immunosuppressive pollutant dioxin, Toxicol. Sci., 79, 304, 2004. 

Although HIV infection inhibition is mainly due to interaction of fullerene derivatives with viral enzymes, it is necessary to consider that this is not the only exploitable mechanism. In fact, the photodynamic inactivation of influenza vims has also been proposed (Zarubaev et al., 2007). The outer viral membrane is destroyed, while it seems that the protein profile of allantoic fluid, in which the vims was propagated, remains unchanged, confirming one more time the great potentiality of fullerene. 

The purpose of the present study was to investigate a photodynamic inactivation of influenza vims in the allantoic fluid of chicken embryos. Further, we have evaluated nonspecific effects of photodynamic treatment on the components of biological fluids. 

The infectious titers of influenza vims were determined in the irradiated specimen at different time points. The kinetics of the vims activity in saline and allantoic fluid in the presence of fullerene and oxygen are presented in Fig. 5.1. 

As can be seen from the data presented, the suspension of crystal C60 did not itself affect the influenza vims. In all control experiments without oxygen and irradiation the infectious activity of the vims remained on the same level throughout the experiment (Fig. 5.1). This was true for both vims in original allantoic fluid and vims resuspended in saline. Exposure of the vims to oxygen without irradiation did not affect the viral titer either. 

In the present study we have investigated the process of photodynamic inactivation of influenza vims in the allantoic fluid of chicken embryos. This inactivation has been realized by C60 water suspension used as a photosensitizer. Similar studies have been carried out previously by Kaserman and Kempf (1997, 1998). Unlike the latter studies, in which viruses were inactivated in salt solutions (buffer), our experiments were performed in a natural biological fluid that contains all typical components (proteins, lipids, salts, etc.). Comparing the viral inactivation over time in our experiments with previous results we conclude that the process described by Kaserman and Kempf (1997, 1998) was more time-consuming, a fact that may significantly restrict its practical use. 

Units and methods are developed to study the effect of active forms of oxygen on fullerene-based photosensitizers. The kinetics of the inactivation of influenza vims in saline and allantoic fluid during the course of photodynamic treatment using fullerene preparations is studied. Optimization of conditions has been conducted for viral inactivation (irradiation, doses, concentration of fullerene, and intensity of oxygen flow). Experiments are performed for inactivation of vims in blood semm. 

Based on optimized conditions, complete inactivation of influenza vims is achieved in allantoic fluid (resulting in a decrease in the infectious titer of the vims from >4-5 log10 EID50 to 0) using separable fullerene-based photosensitizer. 

Certainly, it is not very good when fullerene concentration in C60/PVP complexes is rather low, but let us keep in mind that the acting antiviral dose of fullerene itself in this complex is not high. The active quantity of fullerene, calculated with the neglecting of the polymer vehicle, against the influenza vims is about 7pM (Piotrovskii et al., 2001). 

As seen with the thin films, addition of a competitive small molecule hgand for the vims reduced the CR. Longer UV irradation resulted in the formation of purple hpo-somes that were more sensitive to the influenza vims. The increased sensitivity was suggested to arise as a consequence of the greater degree of polymerization induced by the longer irradiation time. 

In both of these cases, the ligand (sialic acid) for the analyte of interest (influenza vims) was covalently linked to the PDA backbone generated upon photopolymerization. Functional sensors based on ligands that are noncovalently incorporated into liposomes have also been reported (Charych et al. 1996 Pan and Charych 1997). Mixed liposomes as well as mixed thin films on glass containing a combination of the ganglioside GMl and diacetylene lipids detect the presence of cholera toxin, a protein that binds to GMl. 

Back MG, Stevens RC, Charych DH. Design and synthesis of novel glycopol3thiophene assembhes for colorimetric detection of influenza vims and E. coli. Bioconjug Chem 2000 11 777-788. 

Figure 12.4 Colorimetric detection of influenza vims using polymerized liposomes containing sialic acid, (a) Photograph of liposomes to which have been added increasing amounts (from left to right) of influenza vims. Liposomes were 1 and 95% 5. To each well was added the following amounts of influenza vims (left to right) 0, 8, 16, and 32 hemagglutinin units (HAU). Reprinted fi om Charych et al. (1996). Copyright 1996 Elsevier Science.

Colman, P. M. (2005). Zanamivir an influenza vims neuraminidase inhihitor, Expert Review of... 

Baker NJ, Gandhi SS. Effect of Ca++ on the stability of influenza vims neuraminidase. Arch Virol 1976 52 7-18. 

Ward CW, Murry JM, Roxburgh CM, Jackson DC. Chemical and antigenic characterisation of the carbohydrate side chains of an Asian (N2) influenza vims neuraminidase. Virology 1983 126 370-375. 

Wright CE, Laver WG. Preliminary crystallographic data for influenza vims neuraminidase heads JMol Biol 1978 120 133-136. 

Influenza Vims Vaccine, Live, Intranasal (FluMist)... 

Only Type A influenza vims has been found to be capable of producing pandemics. The influenza A virus is identified as a medium-size RNA virus, some lit) nanometers in diameter and delimited by a membrane of lipids and polysaccharides derived from the host cell and virus-specific protein. Five distinct proteins have been identified, three of which are inside the virion. A schematic representation of the influenza virus emerging from a cell is given in Fig. 2. 

Fig. 13. A schematic representation of some key interactions of carboxamide 103 with conserved influenza vims A sialidase active site residues.

---