Treating the flu?
— from “Pale Horse, Pale Rider” by Katherine Anne Porter (1939)
— Revelations 6.8 (King James Version)
Treating the flu? Part 1: The Influenza Virus
|Influenza is caused by RNA viruses of the family Orthomyxoviridae. These virions are roughly 80-120 microns in diameter. Their surfaces consist of a lipid bilayer derived from the membrane of the host cell, which is decorated by glycoproteins that project like spikes from the viral particle. About 80% of these spikes are hemagglutinin, a protein that facilitates binding the virion to a host cell. The remainder areneuraminidase, which is an enzyme that cleaves glycosidic linkages to the sugar neuraminic acid (also calledsialic acid).|
You have probably heard the different strains of the flu virus ("serotypes") referred to as "H1N1" or "H5N1". These names refer to the different subtypes of the two surface glycoproteins, differences that distinguish the serotypes immunogenically.
- Some really nice electron micrographs of real influenza virions that show the hemagglutinin and neuraminidase "spikes".
- Influenza 101 - the virology blog. This takes you through the structure of the virus, how it enters cells, reproduces and then leaves to infect other cells. Very good quality information and very easy reading.
- Influenza Virus from Kimball's Biology Pages
- Influenza viruses on Wikipedia.
Treating the flu? Part 2: Targets for therapy
2. The NA gene. It encodes the neuraminidase.
3. The NP gene encodes the nucleoprotein. Influenza A, B, and C viruses have different nucleoproteins.
4. The M gene encodes two proteins (using different reading frames of the RNA): a matrix protein M1 and an ion channel M2 spanning the lipid bilayer.
5. The NS gene encodes two different non-structural proteins that are found in the cytoplasm of the infected cell but not within the virion itself.
6. – 8. one RNA molecule (PA, PB1, PB2) for each of the 3 subunits of the RNA polymerase.
Treating the flu? Part 3: Neuraminidase
|Recall that the surface of the influenza virion is covered with spikes of hemagglutinin and neuraminidase. Hemagglutinin is a protein that binds tightly to the sugar portions of various cell-surface glycoproteins by recognizing and binding the sugarsialic acid, which is also called N-acetyl neuraminic acid. Sialic acid is found at the terminus of the carbohydrate portions of many cell-surface glycoproteins and plays a key role in cell-cell and cell-virus binding. The human ABO blood-group antigens are examples of sialylated oligosaccharides that play an important role in medical biochemistry.|
Hemagglutinin permits the influenza virus to attach to a host cell during the initial infection, which in turn causes the viral RNA to enter the cell by endocytosis. This is a common mechanism for infection and we know that many viruses including HIV as well as parasites such as the Plasmodium that causes malaria attack host cells via their cell-surface carbohydrates. However, the tight grip of viral hemagglutinin on cell-surface sialic acid is a problem when new viral particles need to break away from the host cell.
|The structure of the influenza A neuraminidase N9 bound to an analogue of sialic acid has been determined by X-ray crystallography, and a simplified ribbon diagram is shown here. The amino acid chains are represented by the yellow ribbons, and the bound inhibitor as well as some key side chain groups are shown in ball-and-stick format. The broad arrows designate regions in which the amino acid chains form a "beta sheet" structure, with the arrow heads indicating the C-terminal end of the sheet. Cylindrical sections represent "random coil" regions of the amino acid sequence. Notice that there is essentially no helical structure in this enzyme. This image shows only one sub-unit of the biologically active form of the enzyme which is actually a tetramer of identical sub-units.|
The binding site of the enzyme does not vary from strain to strain. It consists of 18 amino acid residues of which 12 are in direct contact with the bound sialic acid analogue (and presumably with sialic acid in catalytically active situations). Four of these 12 are positively-charged arginines, while another 4 are negatively-charged glutamic and aspartic acid residues. The remainder are neutral (tyrosine, asparagine, isoleucine and tryptophan).
If you visit the RCSB Protein Data Bank you can find X-ray structures of many neuraminidases - this one is indexed under the code "1nna". The details of the structure are discussed in the original paper by Bossart-Whitaker et al. cited below.