Structure of the 'flu virus |
How the Influenza virus works |
How Relenza works. |
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Fig 5: The Neuraminidase enzyme |
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The enzyme Neuraminidase, also known as sialidase, is a tetramer with C-4 symmetry and an approximate molecular weight of 250 000. It contains a symmetrical folding pattern of six four-stranded antiparallel þ-sheets arranged like propeller blades. Nine types of neuraminidase have been identified for influenza A and only one subtype for influenza B, and only 30% of the overall amino acid sequence is conserved between all known types of neuraminidase8 - these are the amino acids which line and surround the walls of the binding pocket. If they mutate, the enzyme is inactivated, so the virus could not mutate to escape from a drug which interfered with this site. So neuraminidase offers an attractive site for therapeutic intervention in influenza infections. | ||
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Fig. 6: The life cycle of the influenza virus. Click once on this image to see a larger version | |||
The life cycle of the influenza virusG begins with the individual virus entering the cell lining of the respiratory tract (letter a in Fig. 6), and the cell being induced to take up the virus because hemagglutinin on the virus binds to the sialic acid (b and c in Fig 6). The virus then dispatches its genetic material (made up of RNA) and its internal proteins to the nucleus of the cell (e and f). Messenger RNA is produced when some of the internal proteins duplicate the RNA (f). This messenger RNA is used by the cell as a template for making viral proteins (g and h) and genes which become new viral particles and leave the cell covered in sialic acid. This sialic acid needs to be removed so that the hemagglutinin molecules on one particle don't attach to the sialic acid on other ones, thus causing the new viruses to clump together and stick to the cell. The sialic acid is removed from the surface of the new viral particle by neuraminidase (j) and the new viral particles are able to travel and invade other cells (k). |
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Relenza adopts a position within the active site of the enzyme and copies the geometry of the sialoside hydrolysis transition state9. It can achieve very good binding through appropriate presentation of its four pendent substituents and contains a hydrogen bonding glycerol sidechain. The guanidino group in Relenza is believed to form salt bridges with Glu 119 in the neuraminidase active site and add a strong charge interaction with Glu 2278. Two hydroxyl groups of the 6-glycerol side chain are hydrogen bonded to Glu276 and the 4-hydroxyl is oriented towards Glu119. The NH group of the 5-N acetyl side chain interacts with a bound water molecule on the floor of the active site. The carbonyl oxygen of the same side chain is hydrogen bonded to Arg152 and the methyl group enters a hydrophobic pocket lined by Ile222 and Trp178. The glycosidic oxygen projects into bulk solvent. |
Fig 7. Relenza bound to neuraminidase |
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The binding involved in Fig 7 is shown more clearly in Fig 8 below. Neuraminidase can no longer remove the sialic acid receptors from the host cell and newly made virus particles because of this binding. Therefore the virsuse 'clump' together or to the host cell and cannot go on to effect new cells. |
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Fig 8: Depiction of interaction of Relenza (GG 167) in the neuraminidase binding site6 |
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