IV.

Iron Channel Disruptors -Neuraminidase:

Adamantanes has 2 mechanisms of action

Amantadine, Rimantadine, Memantine

at low concentrations: take down the M2 protein/ion

channels:

- block matrix (M2) protein: M2 protein is

responsible for the conformational change of
the viral envelope. When ion channel is
blocked, no conformational change will happen
to the virus -> virus will not be able to enter the
cell membrane

at high concentrations:

- buffer the pH of endosomes: if virus enters the

cell, pH will be lowered and HA will open.
adamantanes have amines which are basic
functional groups -> it will inc pH of cell. if pH
increases, HA will not open. Inside the cell, virus
will just disintegrate without infecting the cell
at low concentrations:
- used against Influenza A only. Influenza B have
different M2 proteins/low M2 proteins to have
significant effect on the virus. Adamantanes
have similar structure with Methenamine.
Neuraminidase inhibitors
Neuraminidase (NA)
- Mushroom-shaped tetrameric glycoprotein: It
has 4 parts.
- Anchored to the viral membrane: anchor is a
single hydrophobic amino acid chain composed
of 29 amino acids. It is bound to the viral
membrane that looks like a mushroom
- active site each monomer in the tetrameric
glycoprotein has an active site. These are deep
pocket located centrally on each protein
subunit. If the tetrameric glycoprotein is isolated
from the anchor, it is still active -> can still
undergo inhibition tests and xray
crystallography to observe binding on the active
site
- Two main types: corresponding to Influenza A
and B. Type C does not undergo variation. B
undergoes minimal. Type A annually undergoes
variation.
-Sialic acid: binds to neuraminidase enzyme. It is a
Pyranose ring. The 6-membered ring in the center is
called tetrahydropyran. Most important functional grp
in the binding is the carboxylate group. Carboxyllic
acid interacts with 3 arginines. Others that interact
with the binding site: 1. glycerol, 2.hydroxy group, 3.
acetamide/ n acetyl group. Methyl group has a
hydrophobic pocket. Hydroxyl group in C-4 is
responsible for 1 hydrophilic interaction.
-the ring interacts via van der waals with the enzyme (not
a significant interaction)
-REMEMBER: One side of the pyranose sugar has
carboxylic acid and an alcohol. If the alcohol is an
OR -. R will be cleaved by NA enzyme. OH has an
interaction with one amino acid and an additional
intramolecular H-bonding with one of the glycerol
alcohols. These improves the conformation of the
ring -> substituents will fit on the binding site
- Chair is the stable conformation but at the binding site it
becomes a pseudo-boat conformation. Why does
this happen -> Axial carboxylate has to react with
arginine that is in an equatorial positon. The axial
carbocxylate has to conform and it moves upward.
- If it is already bound to the active site, the next step
would be an SN1 reaction. The OR will react with
the water molecule. It will be protonated. The lone
pair of O will form resonance to create a more stable
transition state -> it follows the octet rule.
-Sialic acid will be released as an alpha anomer and will
undergo muta-rotation (opening and closing of sugar
rings).
Transition state inhibitors: mimic NA.