Antiviral drugs Flashcards
Why is it difficult to produce anti-virals which are safe for humans?
Viruses utilise cellular functions
Anti-virals which block normal cellular function, would be very toxic
Why does valaciclovir have such a high bio-availability compared to aciclovir?
Aciclovir not asborbed well orally
valaciclovir has a valine group attached, which allows 5x level of absorption
What is the mechanism of action of aciclovir?
Acyclovir is a nucleoside analog related to guanosine, which inhibits DNA polymerase by causing DNA chain termination
It is a prodrug , a precursor of the active antiviral compound.
Conversion to the drug requires the sequential activities of three kinases that produce a triphosphate derivative, the actual antiviral compound
Herpes simplex virus and varicella-zoster virus genomes
encode an enzyme that normally phosphorylates thymidine to form thymidine monophosphate, but this kinase can also accept a wide range of other substrates, including acyclovir.
Cellular enzymes cannot perform this first reaction, but they can synthesize the di- and triphosphates, the latter of which is then used as a substrate by the viral polymerase for incorporation into viral DNA.
As acyclovir lacks the 3-OH group of the sugar ring, the growing DNA chain is terminated upon its addition. The specificity of acyclovir for the herpesviruses depends therefore on the virally encoded thymidine kinase.
How does acivlovir specifically (mostly) only affect virally infected cells?
Viral specific thymidine kinase is required to phosphorylate aciclovir prodrug to aciclovir triphsphospahte - the active form
This substrate is then used by viral polymerase for incorporation into viral DNA
If this viral enzyme is synthesized in an uninfected cell and acyclovir is added, the cell will die because its DNA replication will also be blocked by the chain-terminating base analog. Cells that are uninfected, wont have the thymidine kinase available
What is mechanism of action of ganciclovir?
ganciclovir is a derivative of aciclovir - guanosine analogue
CMV does not carry a thymidine kinase gene, but does encode a protein kinase that can phosphorylate ganciclovir
What is mechanism of action of Zidovudine?
Thymidine analogue causing chain termination
Drug is phosphorylated by cellular enzymes, and then incorporated into viral dNA
phosphorylated zidovudine accumulates in cytoplasm, where reverse transcription of HIV takes place. Therefore it is good at being inserted and causing chain termination
However, it can enter nucleus and cause chain termination of human genes. This is why it causes a lot of side effects
What is the mechanism of action of lamivudine?
nuceloside analogue
phosphorylated by cellular kinases to be incorporated into DNA where it causes chain termination.
Effective at blocking reverse transcriptase of HBV/ HIV
What is the mechanism of action of tenofovir?
nucleotide analogue inhibitor (similar to lamivudine/cidofovir)
What is the mechanism of action of Cidofovir?
nucelotide analogue
prodrug - converted to triphosphate form
has higher affinity for viral polymerase than host polymerase - causes DNA chain termination
What is the mechanism of action of foscarnet?
DNA polymerase inhibitor - non-competitive inhibitor that binds to pyrophosphate binding site of DNA polymerase
Non-nucleoside DNA replication inhibitor - as compared to other herpes drugs which are nuceloside inhbitors
What are foscarnet drug side effects?
nephrotoxic
bone toxicity
only used for life-threatening infections where other antivirals are no longer effective
What is ribavirin mechanism of action?
primary mechanism not entirely clear
interferes with vira-RNA dependent RNA polymerases
causes RNA chain termination
What are some uses of ribavirin?
Primarily RNA viruses, but also effect against some DNA viruses
RSV - aerosol
Lassa
Hanta virus
HCV
What is the mechanism of action of amantadine
Targets influenza A M2 channel protein
M2 channel protein normally allows entry to protons into virus, to allow viral uncoating
High level of resistance around, and side effects including Parkinsonism, so no longer used
What is the mechaism of action of oseltamivir?
neuraminidase inhibitor - prevents neuraminidase cleavage of sialic acid residues from glycoproteins on cells - prevents it from spreading
when given within 48 hours, reduce symptom time by 1 day
When given with 30 hours, reduce symptom time by 3 days
