Antiviral drugs Flashcards

1
Q

What is the feature of a good antiviral drug?

A

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.

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2
Q

Which functions can you target that are unique to the virus

A
Viral entry 
Genome expression 
Replication  
Assembly 
Release
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3
Q

How does HIV enter the cell?

A

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

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4
Q

How can you block virus entry to the host cell?

A

In HIV:

  1. CCR5 antagonists
  2. Fusion inhibitor
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5
Q

How do CCR5 antagonists work?

A

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.

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6
Q

What is the name of a common CCR5 antagonist?

A

Maraviroc

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7
Q

How does a fusion inhibitor work?

A

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.

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8
Q

What is the name of a common fusion inhibitor?

A

Enfuvirtude

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9
Q

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

A

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.

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10
Q

What are common drugs used to inhibit replicatio of viruses?

A

AZT and Acyclovir

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11
Q

How do AZT(Zidovudine) and Acyclovir differ?

A

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.

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12
Q

What type of nucleoside is acyclovir?

A

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

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13
Q

What are other strategies used to block replication?

A

NNRTI - non-nucleoside reverse transcriptase inhibitors
Foscatnet
Ral

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14
Q

How does NNRTI work?

A

Non-nucleoside reverse transcriptase inhibitor

Inhibits reverse transcriptase

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15
Q

How does Foscarnet work?

A

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

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16
Q

How does Tal work?

A

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

17
Q

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

A

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.

18
Q

How do you block assembly of HIV?

A

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.

19
Q

How do you block the release of a virus?

A

Block release by using Neuraminidase inhibitors.

20
Q

How do Neuraminidase inhibitors work?

A

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.

21
Q

What are the flu strains H1N1 and H1N2 named after?

A

The serotype of the surface proteins on their envelope.

22
Q

What is Haemagluttinin?

A

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

23
Q

Example of Neuraminidase inhibitors

A

Tamiflu