Flu (MC)- Block 3

Question 1

What flu types is more prone to frequent antigenic changes?

Answer 1

Type A: responsible for majority of flu epidemics

Question 2

How does flu enter the cell?

Answer 2

Binds to sialic acid on cell surface-> endocytosis

Question 3

What are the outer surface glucoproteins of influenza?

Answer 3

1. Hemagglutinin
2. Neurominidase

Question 4

Types of mutations that lead to antigenic changes of surface proteins?

Answer 4

1. Determinants of antigenicity and host immunity
2. Targets for vaccine (why it changes)
3. Changes in hemagglutinin primarily responsible for evolution of new strains

Question 5

What is the function of HA?

Answer 5

Binding of the virus to cell surface (sialic acid)

Question 6

What is the function of neuraminidase?

Answer 6

Viral surface glycoprotein that functions as a lytic enzyme
* Cleaves sialic acid linkage -> required for release of new viral proteins

Question 7

Diffentiate HA from NA and their properties?

Answer 7

HA: required for host cell binding and internalization
NA: required for new particle release

Question 8

Describe the activity of NA?

Answer 8

Cleaves the glycosidic linkage between sialic acid and glycoprotein -> releasing viral particles from the host cell

Question 9

Describe the MOA of NA inhibitors?

Answer 9

Mimic sialic acid to prevent release of new viral particles, however, virions are still have HA

Question 10

Describe the binding of NA to sialic acid?

Answer 10

Binding at a cationinc and anionic pocket

Question 11

What are the types of NA inhibitors?

Answer 11

1. Zanamivir
2. Oseltamivir
3. Peramivir

Question 12

What is the backbone NA inhibitors must mimic?

Answer 12

Shikimic acid

Question 13

How is Tamiflu more effective than Zanamivir and Peramivir?

Answer 13

4-amino instead of guanidino group to prevent formation of zwitterion and increase bioavailability

Question 14

What NA inhibitors have better binding?

Answer 14

Zanamivir and Peramiver contain a guanadino group perfect for binding, however, it is a strong basic (charged at physiological pH -> protonation) -> poor PO bioavailability

Question 15

Why does Tamiflu have better PO F than other NA inhibitors?

Answer 15

Prodrug: prevents initial zwitterion formation
Primary amine instead of guanadine: not basic and reduces binding capability
3-pentyloxy at C6: Increased lipo (get to suitable log P) offsets the loss of guanadine

Question 16

What are the types of adamantanes?

Answer 16

1. Amantadine
2. Rimantadine

Question 17

MOA of adamantanes?

Answer 17

Target the M2 surface protein (ion channel):
1. Inhibits penetration of RNA virus particles into the host cell
2. Blocks uncoating of the viral genome
3. Can alter pH -> acidic pH needed for uncoating and replication

Question 18

Spectrum of activity for adamantanes?

Answer 18

Only effective against flu A because flu B lacks M2

Question 19

What are the most effective agents against Herpes?

Answer 19

Acyclic nucleosides

Question 20

Describe the MOA of acyclovir?

Answer 20

Prodrug:
1. Phosphorylated to the mono-form by viral thymidine kinase (further converted to di- and tri- phosphates by guanosine monophosphate kinase) - host cell enzyme
2. Competitive inhibitor of viral DNA polymeerase
3. Incorporated as false base into viral DNA by mimicking 2’-deoxyguanosine -> halts further elongation

Question 21

How does acyclovir activated and provide selective toxicity?

Answer 21

Activated by HSV-1 thymidine kinase in infected cells then further phosphorylated by host thymidine kinase
Selective toxicity:
* Creates a high TI

Question 22

What is the active form of acyclovir?

Answer 22

Acyclovir Triphosphate

Question 23

How does valacyclovir differ from acyclovir?

Answer 23

Carrier-linked prodrug through the addition of valine that gets cleaved to become acyclovir

Improves GI absorption

Question 24

Describe the structure of idoxuridine?

Answer 24

Iodine substitution for methyl to mimic pyrimidine nucleoside (2-deoxythymidine)

• Also requires active triphosphate form

Question 25

How does the selectvity of idoxuridine differ from acyclovir?

Answer 25

Host kinase can preform the first phosphorylation making it less selectively toxic but can be cardiotoxic

Question 26

Describe the MOA of idoxurindine?

Answer 26

1. Competitively inhibits HSV DNA polymerase
2. Incorporates as a false base, but DOES NOT halt elongation:
   * Leads to defective protein synthesis and formation of faulty viral proteins
   * Prevents base proper pairing

Question 27

Describe the unique structure of vidarabine?

Answer 27

Adenosine analogue:
1. D-ribose replaced with D-arabinose
2. Can’t be reduced by ribonucleotide reductase or form deoxyribose

Question 28

Describe the MOA of vidarabine?

Answer 28

An inhibitor and substrate of DNA polymerase -> formation of faulty DNA and destabilized strands