Influenza

Question 1

How is the correct nomenclature for influenza and what is the problem with it?

Answer 1

problem: same virus subtype can still be dramatically different

Question 2

What are the main functions of hemagglutinin?

Answer 2

1. receptor binding
   - binds to sialic acids for surface adherence
   - HA1 has RBD -> „head“
2. membrane fusion
   - HA2 has fusion subunit -> „stem“

Question 3

What is neuraminidase good for?

Answer 3

• membrane inserted tetrameric protein
• neuraminidase cleaves sialic acids to detach hemagglutinin and virus from host cell

Question 4

What means balance is key for influenza?

Answer 4

• HA:NA -> binding and release is efficient
• HA>NA -> inefficient entry and release due to too strong binding
• HA<NA -> depleted SA-receptors -> poor binding and inefficient entry

Question 5

How good is the vaccine and what does it contain?

Answer 5

• it varies across years (35-65%)
• contains inactivated 3-4 strains that are picked by experts based on surveillance

Question 6

What are possible drug targets?

Answer 6

• M2 proton channel
• polymerase
• neuraminidase

Question 7

M2 inhibitors in more detail

Answer 7

• amantadine & rimantadin
• inhibit release of RNP within endosome
• quickly acquire resistance
• not used anymore

Question 8

Polymerase inhibitors in more detail

Answer 8

• RdRp essential for transcription and replication
• transcription depends on cap-snatching
• ribavirin -> nucleoside-analogue (depletion of GTP or incorporation leading to error catastrophe)
• favipiravin -> nucleoside-analogue (incorporation into growing RNA-chain, broad spectrum, off-label use in Ebola)
• Baloxavir -> inhibition of cap-snatching by binding to endonuclease of PA-domain of polymerase

Question 9

Neuraminidase inhibitors in more detail

Answer 9

• based on DANA compound
• basic (positive) residue at C4 do Neu5Ac2en leads to favourable interactions with Glu199 and Glu227
• zanamivir (Relenza) and oseltamivir (Tamiflu)