Lecture 7: Influenza

Question 1

Haemaglutinin

Answer 1

→ receptor binding: sialic acid
→ alpha 2,6 and alpha 2,3 linkage
→ sialic acid linked to galactose
→ HA1 domain: receptor binding
→ HA2 domain: fusion

Question 2

Neuraminidase

Answer 2

→ Tetramer
→ Head, stalk, transmembrane and cytoplasmic tail
→ ß-propeller structure
→ active site surrounded by loops thyt connect propeller blades

Question 3

Neuraminidase / Haemaglutinin balance

Answer 3

too much NA:
→ depleted SA-receptors
→ poor binding

too much HA:
→ Inefficient entry, endocytosis, release

balance is key

Question 4

Fusion mechanism

Answer 4

Pre-fusion
→ extended intermediate
→ collapse of intermediate
→ Hemifusion
→ fusion pore

Question 5

Vaccine for Influenza

Answer 5

→ inactivated vaccine with 3-4 strains
→ chosen by expert panel
→ 35-65% efficacy

Question 6

Why is Influenza vaccine so inefficient ?

Whats a promising approach ?

Answer 6

many antigenic sites
→ ones these sites evolve, affinity reduced and vaccine is ineffcient

promising approach/targets
→ receptor binding site as target for broadly neutralizing antibodies
→ stem domain as target for bnAbs

Question 7

Relevant drug targets for Influenzavirus

Answer 7

Replication Inhibitors

Neuraminidase Inhibitors

M2 Inhibitors (Ion channel)

Question 8

M2 Entry Inhibitors

Answer 8

→ proton channel
e.g. Amantadine, Rimantadin
→ inhibit release of RNPs within endosome
→ not good because of resistancy, but repurpose for Parkinson

Question 9

Polymerase Inhibitors
→ mechanism

→ drug and 2 possible mechanisms

Answer 9

RNA Polymerase
→ capped mRNA binds to PB2, then endonuclease activity of PA cuts
→ short capped oligo nt serves as primer for PB1
→ e.g. Ribavirin
→ incorporation into growing viral DNA → term.
→ deleption of GTP pools for guanin
nucleotides
→ Favipiravir
→ nucleoside, broad spectrum

Question 10

Neuraminidase Inhibitors
→ drug mechanism

Answer 10

DANA
→ 4-OH group of DANA, but ….

→ positive charge would help in increase
affinity
→ Zanamivir, Oseltamivir

→ resistancy observed that are inhibitor and subtype specific

Question 11

Which drug class mostly used and why ?

Answer 11

Neuraminidase inhibitors
→ socially targeted antiviral prophylaxis
→ symptomatic individuals and most of close contacts receive treatment → efficient