Antiviral drugs

Question 1

What is the feature of a good antiviral drug?

Answer 1

The key feature of a virus is its dependence on the host cell. Unlike with bacteria therefore, it is difficult to separate the two physiologies between host and pathogen.

A good antiviral distinguishes between the two and targets functions unique to the virus.

Question 2

Which functions can you target that are unique to the virus

Answer 2

Viral entry 
Genome expression 
Replication  
Assembly 
Release

Question 3

How does HIV enter the cell?

Answer 3

HIV is surrounded by spikes, which are comopsed of a trimeric protein with a gp41 transmembrane protein and gp120 surface protein.

gp120 binds to CD 4 coreceptor on T cells and undergoes a conformational change.

This allows the gp120 to bind to chemokine receptors (CCR 5) on the surface membrane of the host cell. This results in further conformational change that exposes the gp41 transmembrane protein.

gp41 is made up of two domains: HR1 and HR2. The hydrophobic terminus of HR1 embeds itself on the hydrophobic ends on the surface of the host cell.

This induces the losely coiled HR2 to pull the two structures together, resulting in fusion of the virus and host cell. HR2 ZIPPING

Question 4

How can you block virus entry to the host cell?

Answer 4

In HIV:

1. CCR5 antagonists
2. Fusion inhibitor

Question 5

How do CCR5 antagonists work?

Answer 5

These molecules mimick the shape of the CCR5 ligand, blocking the receptor from binding to the virus.

This means the fusion of the envelope doesn’t happen.

Question 6

What is the name of a common CCR5 antagonist?

Answer 6

Maraviroc

Question 7

How does a fusion inhibitor work?

Answer 7

Binds to the HR1 hydrophobic terminus of the gp41 transmembrane protein on HIV. Prevent the conformational change so the HR2 is unable to complete HR2 zipping.

Question 8

What is the name of a common fusion inhibitor?

Answer 8

Enfuvirtude

Question 9

What is a common way of blocking replication of a virus?

Answer 9

In normal translation, new genetic strands are made by binding incoming nucleotides to the strand being formed.

This happens via the formation of a phosphodiester bond between the 3’ hydroxyl group and 5’ triphosphate.

Drugs have been developed that lack this 3’ hydroxyl group so the incoming nucleotides can no longer bind to the antisense strand. These are known as CHAIN TERMINATORS.

Question 10

What are common drugs used to inhibit replicatio of viruses?

Answer 10

AZT and Acyclovir

Question 11

How do AZT(Zidovudine) and Acyclovir differ?

Answer 11

AZT treats HIV, Acyclovir treats Herpes infection.

AZT and Acyclovir are given in their unphosphorylated form. They are given without being bound to phosphates, so they first have to be phosphorylated. This phosphorylation only happens in virus infected cells, so it is specific to cells with viral proteins.

AZT is phosphorylated by host proteins quickly, whilst acyclovir depends on viral kinase.

Question 12

What type of nucleoside is acyclovir?

Answer 12

Acyclovir is a guanosine derivative lacking the 3’ OH group.

Question 13

What are other strategies used to block replication?

Answer 13

NNRTI - non-nucleoside reverse transcriptase inhibitors
Foscatnet
Ral

Question 14

How does NNRTI work?

Answer 14

Non-nucleoside reverse transcriptase inhibitor

Inhibits reverse transcriptase

Question 15

How does Foscarnet work?

Answer 15

Blocks pyrophosphate on DNA of Herpes virus. Prevents the incoming nucleoside from forming phosphodiester bonds since the recruitment of the triphosphate form is blocked.

Question 16

How does Tal work?

Answer 16

Inhibits integrase so the newly synthesised viral DNA is not integrated into the host genome.

Question 17

How have drug manufacturers overcome the low bioavailability of these drugs?

Answer 17

By binding the complexes with amino acids .

Conjugation turns Acyclovir into Val-Acyclovir once bound to Valine.

This is done via an ester link.

The Val-Acyclovir is processed by esterases to form Acyclovir.

Question 18

How do you block assembly of HIV?

Answer 18

HIV assembly is blocked by protease inhibitors.

In order to form mature HIV viral proteins, GAG has to be cleaved off the polyploid immature protein.

This is done by a dimeric aspartic protease sitting on active site of protease.

Question 19

How do you block the release of a virus?

Answer 19

Block release by using Neuraminidase inhibitors.

Question 20

How do Neuraminidase inhibitors work?

Answer 20

Viral proteins bind to the CSM of host cells by forming bonds with sialic acid via Haemagglutinin.

The neuraminidases cleave this bond to allow the viruses to transmit to other cells.

Neuraminidase inhibitors therefore prevent sialic acid being cleaved off the host cell and so viruses remain bound.

The inhibitors bind to the active site of the neuraminidase enzyme.

Question 21

What are the flu strains H1N1 and H1N2 named after?

Answer 21

The serotype of the surface proteins on their envelope.

Question 22

What is Haemagluttinin?

Answer 22

They are fusion proteins that recognise sialic acid receptors on target cells. Once bound to sialic acid, they are absorbed by cell via endosome.

Question 23

Example of Neuraminidase inhibitors

Answer 23

Tamiflu