Lecture 2 - Antiviral agents

Question 1

Describe the mechanism of action of Aciclovir (antiviral)

Answer 1

Aciclovir is phosphorylated three times to form aciclovirtriphosphate (nucleotide) which competes with GTP and introduced into the viral genome. Aciclovirtriphosphate then inhibits viral DNA polymerase which causes the viral DNA chain to be terminated.

Question 2

Why does Aciclovir not affect all human cells?

Answer 2

Aciclovir can only be phosphorylated (first phosphorylation) by a thymidine kinase enzyme found in HSV and VSV therefore only viral infected cells can activate Aciclovir

Question 3

Name three properties of Aciclovir that ensures its selectivity to viral cells

Answer 3

• only activated in viral cells
• becomes concentrated in viral cells
• it has a higher affinity for viral DNA polymerase than cellular enzymes

Question 4

Describe the three mechanisms for Aciclovir resistance

Answer 4

1) No TK enzyme cant phosphorylate the drug
2) TK mutates and cant phosphorylate the drug
> both of these non pathogenic as if no working TK cant cause disease
3) altered DNA polymerase cant bind to Aciclovirtriphosphate (common with frequent HSV infection e.g. AIDS)

Question 5

When is Ganciclovir used? how does it work?

Answer 5

• CMV (also active against HSV)

- same mechanism as aciclovir but in CMV, first phosphorylation is done via UL92 enzyme in CMV

Question 6

two negatives to Ganciclovir

Answer 6

• poorly absorbed

- also phosphorylated in some host cells causing toxicity e.g. in bone marrow

Question 7

When is Cidofovir used? how does it work?

Answer 7

• CMV although can be used broad spec for any DNA virus’
• already phosphorylated once therefor non viral dependent phosphorylation, inhibits DNA polymerase. Works on the princible that the triphosphate will have a greater affinity for viral dna polymerase than human dna polymerase

Question 8

One negative to Cidofovir

Answer 8

causes toxicity as can be phosphorylated by all host cells.

Question 9

How does Foscarnet work? What does it target ? Two negatives?

Answer 9

• it inhibits viral DNA polymerase (phosphate analogue)
• used for CMV
• poor oral availability and nephrotoxic

Question 10

What is Penciclovir and how does it work?

Answer 10

• same as aciclovir but doesnt terminate the DNA chain

- HSV and VSV

Question 11

How does Ribavirin work? When is it used?

Answer 11

mode is unknown

• severe RSV (given by inhilation)
• Lassa fever
• Chronic Hep C (and interferon gama)

Question 12

What does amantidine do? Why is it no longer used?

Answer 12

inhibits influensa A by uncoating virus.

Poorly tolerated by elderly due to CNS side effects/neurotoxicity (also treats parkinsons)

Question 13

What are zanamacir and oseltaminivir ? how do they work?

Answer 13

Neuraminidase inhibitors. Neuraminidase usually cleaves the viron from the viral envelope once budded to allow release of viron. Without this cells cant replicate.

Question 14

What virus does zanamacir and oseltaminivir work against?

Answer 14

ALL influenzas (stock piled loads incase of flu epidemic)

Question 15

What is valaciclovir?

Answer 15

esterified aciclover which has better oral absorbtion

Question 16

Name types of HSV virus that you would treat with Aciclovir

Answer 16

1) primary oral herpes gingivistomatitis
2) Genital herpes
3) Corneal - can cause blindness (treat with steroids also)
4) encephalitis (can cause brain necrosis - emergency , treat before confirm diagnosis) (iv)
5) eczema herpeticum - can spread across skin potentially life threatening, treat ASAP

Question 17

When would you not use Aciclovir to treat HSV

Answer 17

coldsaws - only reduces infection time by 24h

recurrent genital herpes (although can use as prophylaxis if severely immunocompromised and frequent reinfection)

Question 18

When would you use Aciclovir to treat VSV

Answer 18

1) Adult VSV (shingles - can cause pneumonia potentially life threatening)
2) Adult VSV in pregnancy when life threatening sepsis
3) Virus can stay latent in cranial nerves - if any shingles on forehead treat as can cause ulceration of cornea
4) Any shingles in immunocompromised patients treat immediately

Question 19

When would you not use Aciclovir to treat VSV

Answer 19

1) chicken pox in children

2) pregnancy unless life threatening

Question 20

Name the three mechanisms of antiviral drugs

Answer 20

DNA/RNA synthesis inhibitors
Uncoating inhibitors
Neuraminidase inhibitors

Question 21

Common manifestation of CMV in patients with HIV? how would you treat this ?

Answer 21

• CMV retinitis > can cause blindness

- ganciclovir or cidofovir