Antivirals

Question 1

HSV-1 vs HSV-2

Answer 1

1 = orolabial herpes
2 = genital herpes

Question 2

How do herpesvirus drugs become active?

Answer 2

they are prodrugs that need phosphates to be active (become triphosphates)

Question 3

mechanism of action of guanosine analogs

Answer 3

• triphosphate forms inhibit viral DNA synthesis
• -competition w/ dGTP in *binding to viral DNA polymerase and polymerase inhibition
• -*terminate viral DNA chain following incorporation
• *metabolic activation requires viral enzyme like HSV thymidine kinase

Question 4

*How does resistance to acyclovir occur?

Answer 4

in HSV or VZV through alterations in viral thymidine kinase or DNA polymerase, mainly in immunocompromised pts

Question 5

mechanism of action for CMV nucleoside analogs

Answer 5

competition w/ GTP in binding to viral DNA polymerase and polymerase inhibition; *conversion to nucleoside monophosphate requires CMV kinase UL97

Question 6

acyclovir vs ganciclovir for CMV tx

Answer 6

ganciclovir activity against CMV is 100X that of acyclovir

Question 7

explain resistance to ganciclovir

Answer 7

*resistance via mutation of CMV kinase gene UL97 or viral DNA polymerase gene UL54

Question 8

mechanism of action of foscarnet

Answer 8

blocks pyrophosphate binding site of polymerases; inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates

Question 9

How do HIV drugs elicit selective toxicity?

Answer 9

via interference with:

• viral binding/membrane fusion
• viral reverse transcriptase-mediated duplication
• integration of viral DNA into host chromosomes
• processing of viral proteins

Question 10

*standard retroviral drug therapy

Answer 10

• -*combo therapies of at least 3 drugs (HAART)
• -*reduce viral replication to the lowest possible level & decrease the emergence of resistance
• -*tailored to individual patient and to drug sensitivities of the specific viral variant (genotype)
• -*modified in response to sensitivity (genetic evolution of drug resistance)
• -designed to *maximize tolerability, convenience, & adherence to regimen

Question 11

What are NRTIs?

Answer 11

nucleoside/nucleotide reverse transcriptase inhibitors (ex: zidovudine/*AZT)

• -*inhibit the conversion of viral ssRNA to proviral dsDNA
• -**compete w/ deoxynucleotide substrates in binding to the polymerase
• -lack of 3’-hydroxyl causes **chain termination

Question 12

mechanism of action of NNRTIs

Answer 12

inhibit retroviral RT activity; *binding site of NNRTIs distinct from that of NRTIs; **allosteric inhibitors so don’t compete w/ nucleoside triphosphates nor require phosphorylation

Question 13

mechanism of action of PIs

Answer 13

protease inhibitors prevent cleaving of polyprotein precursors during maturation; *leads to production of immature, noninfectious viral particles

Question 14

**booster therapy

Answer 14

inhibition of CYP3A4 by a PI can enhance the conc of another retroviral drug in combo thus resulting in synergy

Question 15

mechanism of action of integrase inhibitor

Answer 15

block integration of proviral DNA into host genome; *bind/inhibit viral integrase enzyme