Flu (MC)- Block 3 Flashcards
What flu types is more prone to frequent antigenic changes?
Type A: responsible for majority of flu epidemics
How does flu enter the cell?
Binds to sialic acid on cell surface-> endocytosis
What are the outer surface glucoproteins of influenza?
- Hemagglutinin
- Neurominidase
Types of mutations that lead to antigenic changes of surface proteins?
- Determinants of antigenicity and host immunity
- Targets for vaccine (why it changes)
- Changes in hemagglutinin primarily responsible for evolution of new strains
What is the function of HA?
Binding of the virus to cell surface (sialic acid)
What is the function of neuraminidase?
Viral surface glycoprotein that functions as a lytic enzyme
* Cleaves sialic acid linkage -> required for release of new viral proteins
Diffentiate HA from NA and their properties?
HA: required for host cell binding and internalization
NA: required for new particle release
Describe the activity of NA?
Cleaves the glycosidic linkage between sialic acid and glycoprotein -> releasing viral particles from the host cell
Describe the MOA of NA inhibitors?
Mimic sialic acid to prevent release of new viral particles, however, virions are still have HA
Describe the binding of NA to sialic acid?
Binding at a cationinc and anionic pocket
What are the types of NA inhibitors?
- Zanamivir
- Oseltamivir
- Peramivir
What is the backbone NA inhibitors must mimic?
Shikimic acid
How is Tamiflu more effective than Zanamivir and Peramivir?
4-amino instead of guanidino group to prevent formation of zwitterion and increase bioavailability
What NA inhibitors have better binding?
Zanamivir and Peramiver contain a guanadino group perfect for binding, however, it is a strong basic (charged at physiological pH -> protonation) -> poor PO bioavailability
Why does Tamiflu have better PO F than other NA inhibitors?
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
What are the types of adamantanes?
- Amantadine
- Rimantadine
MOA of adamantanes?
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
Spectrum of activity for adamantanes?
Only effective against flu A because flu B lacks M2
What are the most effective agents against Herpes?
Acyclic nucleosides
Describe the MOA of acyclovir?
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
How does acyclovir activated and provide selective toxicity?
Activated by HSV-1 thymidine kinase in infected cells then further phosphorylated by host thymidine kinase
Selective toxicity:
* Creates a high TI
What is the active form of acyclovir?
Acyclovir Triphosphate
How does valacyclovir differ from acyclovir?
Carrier-linked prodrug through the addition of valine that gets cleaved to become acyclovir
Improves GI absorption
Describe the structure of idoxuridine?
Iodine substitution for methyl to mimic pyrimidine nucleoside (2-deoxythymidine)
- Also requires active triphosphate form
