8 Antivirals

Question 1

why are the less antiviral drugs

Answer 1

Not as many antiviral drugs as there are antibacterials - as viruses can only replicate in living cells

Question 2

what do viruses use to replicate

Answer 2

Use cellular machinery to do all the processes that are necessary to replicate the virus

Question 3

what do viruses effect

Answer 3

Interfere with the host cell – kill host cell = kill virus (isn’t useful clinically)

Question 4

Schematic virus replication cycle

Answer 4

1. Attachment
2. Entry
3. Uncoating
4. Macromolecular synthesis
5. Assembly
6. Release

Question 5

Acyclovir drug

Answer 5

first proof that drug can interfere with virus and not harm host

Question 6

what does ACV interfere with

Answer 6

DNA synthesis

cause termination of DNA synthesis as nothing for next base to come into – when part of the chain

Question 7

what is ACV

Answer 7

analogue of guanosine

Question 8

what is the ACV active form

Answer 8

Adding 3 phosphate to ACV – eukaryotes cannot do this but if infected with virus that has particular enzyme then these virally encoded enzymes can phosphorylate ACV

Question 9

what does ACV compete with

Answer 9

guanosine triphosphate to get into growing DNA chain (to terminate) this molecule is recognized much better by viral DNA enzymes compared to host cell DNA enzymes – selectively antiviral

Question 10

ACV: selectivity of action

Answer 10

• Only activated in infected cells
• Becomes concentrated in infected cells
• Higher affinity for viral DNA polymerase than cellular enzymes

Question 11

what activates ACV

Answer 11

viral enzyme – thymidine kinase

Question 12

ACV spectrum of activity

Answer 12

NARROW only works against – but they’re pretty common (HSV herpes virus, VZV) Will only work against a virus with both thymidine kinase to phosphorylate it and a DNA polymerase

Question 13

ACV: resistance

Answer 13

thymidine kinase absence
- exist pretreatment and are selected for
- but are non-pathogenic
Alteration of thymidine kinase – TK mutants
- Do appear during therapy
- but are also of attenuated virulence
Altered DNA polymerase
- Fully virulent, and a real clinical problem

Question 14

what drug is dervived from ACV

Answer 14

Valine ester of ACV

Question 15

how is valine ester ACV administered

Answer 15

orally

Question 16

what happens when valine ester ACV is taken

Answer 16

breaks into ACV and valine

Question 17

which drug is better ACV or valine ester ACV

Answer 17

Valine ester is much better - most 3x a day or 1x a day (better blood levels)

Question 18

Anti-cytomegalovirus drugs

Answer 18

Ganciclovir
Cidofovir
Foscarnet

Question 19

what is Ganciclovir

Answer 19

Acyclic guanosine analogue

Question 20

what does ganciclovir require

Answer 20

phosphorylation – by the gene UL97

Question 21

what does ganciclovir inhibit

Answer 21

acts as DNA polymerase inhibitor

Question 22

what is ganciclovir active against

Answer 22

all herpesviruses

Question 23

why was valganciclovir made

Answer 23

ganciclovir poorly absorbed orally

Question 24

con of ganciclovir

Answer 24

Toxic e.g. bone marrow suppression– easier to phosphorylate so host start to

Question 25

what is cidofovir

Answer 25

Acyclic phosphonate nucleotide analogue | has a phosphate group on it already

Question 26

what does cidofovir require

Answer 26

Non-viral dependent phosphorylation

Question 27

what does cidofovir inhibit

Answer 27

viral DNA polymerase

Question 28

what is the benefit of cidofovir

Answer 28

Broader spectrum – potentially all DNA viruses

Question 29

how is cidofovir administered

Answer 29

Given by intravenous infusion (not given orally) given by inject once a week

Question 30

con of cidofovir

Answer 30

Toxicity VERY as host can easily phosphorylate (phosphate already there) – nephrotoxic – secreted into renal tubules and damages them = kidney damage

Question 31

what is foscarnet require

Answer 31

doesn’t need to be phosphorylated by anything

Question 32

what is CMV

Answer 32

mostly harmless virus

Question 33

when is CMV harmful

Answer 33

crosses the placenta in pregnant women will damage the foetus or if immunosuppressed CMV is a multisystem pathogen

Question 34

CMV and HIV

Answer 34

HIV immunosuppressed CMV common - better HIV treatment now that they will unlikely reach the immunosuppressed stage to get CMV and then latent reinfection

Question 35

Ribavirin effect

Answer 35

Don’t know for sure how this drug works | ? Interferes with 5’ capping of mRNA processing (recognised by the ribosome)

Question 36

ribavirin benefit

Answer 36

If effects mRNA processing – all viruses have to make mRNA and get onto ribosome to make viral protein = broad spectrum of activity in vitro, incl both DNA and RNA viruses

Question 37

what are the uncoating inhibitors

Answer 37

- Amantadine | - rimantadine

Question 38

what does amantadine inhibit

Answer 38

uncoating of influenza A virus

Question 39

what is the problem with amantadine

Answer 39

- Poorly tolerated because of CNS stimulation - Resistance rapidly emerges - No longer recommended

Question 40

how does amantadine work

Answer 40

hydrogen ions enter through ion channel | blocks the ion channel – blocks the acidification of the viral capsid = prevents uncoating

Question 41

how do neuraminidase inhibitors work

Answer 41

Virus has hemagglutnin on its surface and cell trying to leave has sialic acid – virus would get stuck when trying to bud out Neuraminidase cleaves sialic acid, allow virus get away, can infect more respiratory epithelial cells Block neuraminidase then can stop the virus going to infect another cell can’t carry on replicating

Question 42

what are the neuraminidase inhibitors

Answer 42

Zanamavir

Question 43

what do neuraminidase inhibitors work against

Answer 43

against all known influenza NA (all viruses have a hemagglutnin and neuramnidase –inhibit all the NA)