Lecture 4 Antivirals against influenza virus Flashcards
Name the 3 components that classify the influenza virus
RNA
-ve stranded
segmented
Orthomyxoviridae
How many flavours of influenza are there?
3 - influenzavirus A-C
Which is the most common influenza in humans?
Influenzavirus A
What flavour does the Australian flu come under?
Influenzavirus B
What is the lipid bilayer of the virus made from?
plasma membrane of the previously infected cell
Which variant M glycoproteins does influenzas A-C encode for?
Influenza A = AM2 protein
Influenza B = BM2 protein
Influenza C = CM2 protein
What is the difference between low pathogenicity seasonal flu and high pathogenicity influenza strains?
low pathogenicity seasonal flu - mild and common type of flu
high pathogenicity influenza strains - rare and severe, can cause deaths
name 2 examples of high pathogenicity influenza strains
Avian influenza (H5N1) Spanish influenza (H1N1)
How is influenza virus transmitted?
Droplet inhalation - sneeze, cough, breathing = small droplets enter the resp tract
Direct contact - sneezing, coughing and breathing = droplets on surfaces called fomites, contact between surfaces and mucosal cells, mediated by contaminated hands/fingers
What are the symptoms of influenza virus?
Upper resp tract cells affected Symptoms have rapid onset (24h after contact), peak at day 3, persist for 8/9 days Tiredness Sore throat Runny nose Headache Fever Cough Muscle aches
What are the 3 membrane proteins on the influenza virus?
M2 protein - specific to flavour of influenza
Neuraminidase (NA)
Haemoglutanin (HA)
What shape is the influenza virus?
Rod shaped
What is the the matrix protein?
The sheeth beneath the membrane [see slide for image]
Describe the influenza virus life cycle
[see slide for image]
Virus binds sialic acid receptor via HA, becomes internalised → Low pH membrane fusion via HA → segments released into cytoplasm → segments imported into nucleus → RNA synthesis → RNA/RNP export → virus assembly at plasma membrane → release of viron
Explain step 1 virus attachment of influenza virus
HA recognises sailic acid on the surface of cilliated epithelial cells
HA binds to sialic acid via galactose protein
Explain step 2/3 virus entry of influenza virus
Virus is inside the endosome
Escapes when virus envelope (matrix layer) fuses with endosome membrane - mediated by HA protein changing confirmation due to low pH
8 RNA protein segments still cannot get out - release is mediated by M2 protein
M2 (ion channel) forms a pore = influx of H+ ions
Matrix protein layer breaks down and segments are released [see slide for image]
Explain step 8 virus release of influenza virus
Virus now needs to infect new cells via HA and sialic acid receptor
Need to make sure that HA on released viruses does not bind to receptor on the old cell as this would mean the virus does not spread
Controlled by the NA protein on the virus cell membrane
NA cleaves sialic acid from previously infected cell (essential role)
[see slide for image]
Why is a new vaccine needed for influenza every year
Influenza virus is rapidly mutating
Every year there is a different strain of the virus
Why is a stockpile of antiviral medication for influenza needed despite there being vaccines?
Vaccine is slow to make - 9 months
If a pandemic occurred then it would not be quick enough to make a vaccine
Antiviral would work against many strains
Name the 2 ways that influenza virus mutation occurs
Antigenic drift
Antigenic shift
What is antigenic drift?
When enzyme genes are copied, mistakes are made
Incorporation of single nucleotide changes into genome
Leads to new virus formation
What is antigenic shift?
Occurs when 2 different cells infect the same virus
Allows genome segments to mix when virus assembly occurs = different proteins encoded
What are the 2 current targets for influenza antivirals?
M2 protein
Neuraminidase cleaving protein
What are 2 names of drugs in the adamantanes class?
Amantadine
Rimantadine
Which influenza families does adamantanes target?
Low conc = specific for influenza A
High concentration = some general antiviral activity
What are the pros of adamantanes?
Cheap
Effective
Given as oral or aerosol
What are the cons of adamantanes?
Must be administered early before the infection e.g. before day 2
Most influenza viruses now resistant due to drift mechanism - mutation in M2 channel
Therefore no longer approved by FDA to treat influenza
What is the mechanism of action of adamantanes?
Prevent M2 ion channel activity Blocks either of the 2 binding sites: Within the central pore Within a membrane facing pocket - one of each of the monomers of the tetramere = prevention of ion channel activity Matrix layer remains intact Virus cannot exit the endosome
What is the mechanism of action of Relenza (zanamir) and oseltamivir (tamiflu)?
Mimic sialic acid - blocks neurominidase active site so it can no longer bind and digest sialic acid
Produced based on the contact sites between the sailic acid in the neurominidase active state
Produced a molecule that bound with a higher affinity by adding a guanidino group to Glu119 at C4 = now interacts with Glu 225 and Asp 151
Do neurominidase inhibitors work?
Moderately
Must be given very early on in infection i.e. 48 hours
Symptoms are reduced by 1 day = little impact
Is it worth it? well it may be enough to slow pandemic spread
Stockpiles of Relenza (zanamir) and oseltamivir (tamiflu) exist
Are neurominidase inhibitors at risk of resistance?
Should not encounter resistance problems as similar structure to sailic acid
However 1% of seasonal strains have shown resistance
