Chapter 36 - Antiviral Chemotherapy

Question 0

PLECONARIL

Answer 0

PICORNAVIRUS
- capsid-binding drug preventing ATTACHMENT

• displaces hydrophobic lipid, altering structure of canyon of VP1 therefore PIcornavirus receptor won’t fit into vp1 canyon

Question 1

MARAVIROC

Answer 1

• Attachment
• HIV
• prevents HIV virion attachment of MACROPHAGE coreceptor CCR5 from binding to CD4

Question 2

ENFUVIRTIDE

Answer 2

• ANTI VIRUS ENTRY
• HIV
• HIV envelope binding drug
• FUSION inhibition by HIV gp41 (TM) block so no fusion mediation occurs

Question 3

AMANTADINE

Answer 3

• Virus UNCOATING antiviral drug
• Influenza A
• blocks H+ pump ion Channeling ie.
• targets M2 (integral membrane protein) and blocks it so no protons can enter virus
• blocks pH drop

Question 4

How to detect genotype when you know the phenotype?

Answer 4

Isolate drug resistant virions - mutants - map segment that’s different from WT and sequencing back for eg. To M2 gene!

Resistant HIV strains to ritonavir have mutations in their protease- no enzymatic approaches to cleave gag to maturation

Question 5

ACYCLOVIR
+
Ganciclovir

Answer 5

• nucleoside analog targeting viral DNA pol!
• anti Herpesvirus
• dG analog COMP INHIB.
• drug has 5’OH that gets triphosphorylated
• CHAIN TERMINATOR
• toxic if cPol uses it
• viral ns kinase phosphorylating drug more efficiently than cellular ns kinase
• viral polymerase using drug more efficiently than cellular polymerase

Question 6

ACYCLOVIR

Answer 6

Preferentially phosphorylated in cells infected with herpes virus
- NOT efficiently mono phosphorylated at alpha P by viral TK so HSV TK.
- Preferentially blocks HSV DNA pol and this uses little cDNA pol to form triPh.
So drug competes with pppdG to replace it by pppACV into HSV DNA pol –> frozen pol.

Question 7

AZIDOTHYMIDINE

Answer 7

• nucleoside analog targeting viral DNA pol
• HIV
  Used with combo of other HIV drugs as part of HAART
  -AZT mono phosphorylated by CELLULAR TK –> this form BLOCKS cellular thymidylate kinase that adds beta P to mono.
  = TOXIC for cell
  Eventually, less AZT administered so triphosphorylated form arises which has HIGH selectivity for HIV RT versus cellular Pol.
• rational design dev

Question 8

NEVIRAPINE

Answer 8

-GENOME REPLICATION
- HIV!!
- non ns analog
Inhibits RT
Binds close to active site –> allosteric effect on RT

Question 9

RALTEGRAVIR

Answer 9

• Genome replication inhibitor
• HIV
• allosteric effect on INTEGRASE

Question 10

RITONAVIR

Answer 10

• involved in maturation inhibition
• HIV!!!
  Peptidomometic
• binds to protease active site preventing GAG cleavage by competitive inhibition and therefore maturation of Gag poly protein so gag’s phe-pro bond cannot be broken

Question 11

OSELTAMIVIR

Tamiflu

Answer 11

• blocks virion Release
  Influenza A and B
  NA inhibitor!!!

Inhibits neuraminidase via structural mimicking of sialic acid

Result: stops release of influenza virion from cells and prevents their spreading from mucous to respiratory tract.

Question 12

ZANAMIVIR

Answer 12

• release block
• influenza A and B
• same as oseltamivir
  Blocks NA activity by mimicking SA and inhibiting release and spread of virion

Question 13

Acyclovir and ganciclovir depend on what?

Answer 13

1) viral nucleoside kinase that phosphorylating the drug MORE efficiently than cellular nucleoside kinase.
2) viral polymerase using the drug as a pppdG analog more efficiently than cellular polymerase
(Why? To reduce toxicity by increasing specificity for viral pol)

Question 14

When is acyclovir efficiently phosphorylated with alpha- P?

Answer 14

When cells are infected with herpesvirus

Mono phosphorylation of acyclovir is inefficient in uninflected cells.

Question 15

Can pppACV bind to one nucleoside prior to chain termination?

Answer 15

Yes.

pppdC binds and then viral (herpesvirus) DNA pol stalls.

Question 16

What enzyme does AZT use to become mono phosphorylated?

What effect does this have on patient?

Answer 16

Cellular TK

Toxic for patient because AZT mono phosphate BLOCKS cellular thymidylate kinase in all cells!
So for a short time frame, when AZT mono phosphate levels are high - prior to triphosphorylation- This inhibition will be toxic.

Question 17

What are the two functions of AZT triphosphate?

Answer 17

1) Viral RT comp. inh.
2) chain terminator

Also it is highly selective for RT so does not interact with cellular polymerase.

Question 18

How many HIV antiviral drugs are to be known?

Answer 18

6 out of the 11

Maraviroc
Enfuvirtide
Azidothymidine
Nevirapine
Raltegravir
Ritonavir