Antivirals Flashcards
Viral replication is so intimately associated with the host cell that any drugs that interferes significantly with viral replication is …
likely to be toxic to the host
What is the most severe constraint limiting the use of antiviral drugs?
The toxicity to the mammalian cells, not the lack of efficacy
A successful antiviral drug should …
interfere with a virus-specfic function
either because the function is unique to the virus or the similar host function is much less susceptible to the drug
Aside from interfering with a virus specific function, what else can an antiviral do?
interfere with a cellular function necessary for viral replication
in this case, to be specific the antiviral drug must only affect virus infected cells - specificity could be obtained by restricting drug activation to virus-infected cells
What are the possible targets for antiviral therapy?
- prevention of entry into host cell
- Inhibition of virus uncoating
- integrase inhibitors
- duplication of the viral genome
- mRNA transcription and processing
- protein translation
- post-translational modification of proteins
- assembly of the components into the whole virus
How can we target/prevent the the virus from entering into host cells? (think HIV)
- inhibitors of attachment that compete with a viral receptor
- coreceptor antagonists
- fusion inhibitors that prevent fusion with host cells
What is maraviroc?
CCR5 coreceptor antagonist - used to prevent entry of HIV into host cells
should only be used in CCR5-trophic patients
How can HIV resist maraviroc?
by using the drug-bound form of CCR5 as a coreceptor — this is called noncompetitive resistance
What CYP is maraviroc metabolized by?
CYPA3
so adjust dose when used with drugs that inhibit or stimulated this enzyme to adjust for changes in metabolism
What is Enfuvirtide (T-20)?
a fusion inhibitor used for HIV because is specifically inhibits the function of gp41
it is derived from the natural gp41 HR2 sequence
When does viral uncoating occur?
at low pH at the level of endosomes or lysosomes (pH-dependent uncoating)
— note: this is different than fusions, which is pH-independent
What do integrase inhibitors do?
prevent the insertion of the virus genetic code into the DNA of infected cells by inhibiting the viral integrase
What class of drugs contain the best antiviral drugs available? Why?
Drugs that target duplication of the viral genome (aka polymerase inhibitors)
Drugs from this class are selective! b/c
- virus may used its own enzyme to activate the drug AND/OR
- viral polymerases are much more sensitive to the drug than the corresponding host enzyme
What is thymidine kinase encoded by some viruses used for? How is it pharmacologically relevant?
used in the synthesis of their DNA
it can activate some drugs in the class that target duplication of the viral genome (why? b/c it lacks specificity)
What classes of drugs does interferon fall in?
mRNA and transcription processing
AND protein translation
(note - it acts nonspecifically)
What are the post translational modifications that can be targeted?
glycosylation
phosphorylation
fatty acylation
What do neuraminidase or sialidase do?
help spread the influenza virus from cell to cell by removing sialic acid from the surface (at the level of the glycoproteins and glycolipids) of infected cells so that viral particles may escape
What is zanamivir?
a potent inhibitor of viral neuraminidase of type A and B influenza
What kind of drugs are protease inhibitors? (aka what do they do?)
block assembly of the molecular components into the whole virus
What antiviral drugs target uncoating?
Amantadine
Rimantadine
What antiviral dugs act as DNA or RNA polymerase inhibitors?
Idoxuridine (used topically)
Trifluridine (used topically)
Cytarabine
Vidarabine
Ribaviron
Acyclovir
Ganciclovir
AZT
Acyclovir
- activated by
- why is it advantageous?
- how does it act?
its a purine analogue that competes with dGTP
activated by phosphorylation
its very sensitive
binds the active site of DNA pol and also acts as a chain terminator (it does not have a 3’ hydroxyl)
AZT (azidothymidine or zidovudine)
- what kind of drug is it?
- is it active upon administration?
- why is it specific?
A chain terminator
its a prodrug and needs to be phosphorylated to become active
Reverse transcriptase (RNA-dependent DNA polymerase) is more sensitive to the drug than DNA-dependent DNA polymerase
There is an increased risk for side effects with AZT when used with …
WHY?
drugs that interact with glucuronyl transferase pathway - e.g. aspirin, acetaminophen, indomethacin
aspirin goes first in using this enzyme.. so AZT has to wait and increased concentrations in the body leads to increased toxicity
Interferons act as several levels of RNA and DNA virus replication…
- enhance the specific immune response (increase MHCI expression on infected cells)
- direct antiviral effects
Asuprenivir - what are the hopes with this?
hope that it will allow interferon-free tx of hep C
What do protease inhibitors do?
Prevent the maturation of viral particles
Ritonavir
Used to increase the efficacy of other drugs
Alpha and beta interferons bind to…
Receptors on adjacent cells (after being secreted by virus infected cells) and prevent them from viral infection
They enhance the expression of MHC I and II
–enhances presentation of viral antigens
Gamma interferon
Secreted by t lymphocytes
Enhance T cell medicated immune response
