Antivirals 1 Flashcards
Anti-herpesvirus agents
Acyclovir
valcyclovir
Famciclovir (active form penciclovir)
ganciclovir
Valganciclovir
foscarnet
Cidofovir
Letermovir
Acyclovir and valcyclovir MOA
Competitivley inhibit DNA polymerase and incorporates self into DNA strand leading to early chain termination
Both Pro-drugs
Famciclovir and penciclovir MOA
Activated by cellular and viral kinases and competitively inhibit viral DNA polymerase
DO NOT cause immediate chain termination (known as short chain terminators)
Ganciclovir and Valganciclovir MOA
Better for CMV
Activated by cellular and viral kinases and competitively inhibit viral DNA polymerase
DO NOT cause immediate chain termination
resistance due to mutation in CMV kinase or CMV DNA pol - not cross resistant to cidofovir or foscarnet
Foscarnet MOA
Inhibits viral DNA polymerase, blocks pyrophosphate binding site of viral DNA polymerase, traps polymerase in closed conformation leading to inability of DNA to translocate
the foscarnet is trapping the dna polymerase in a closed position so it can’t move to the next base to add to chain
inhibits cleavage of pyrophosphate from dNTPs
Cidofovir
Competitive DNA polymerase inhibitor and chain terminator
used in CMV
very broad spectrum
Letermovir - non-nucleoside
binds to pUL56 and prevents cleavage and packaging of Herpes
- no cross resistance between other CMV drugs
Be able to explain why viral thymidine kinase mutants resistant to ganciclovir are not resistant to cidofovir or foscarnet. Why are foscarnet-resistant viruses likely to be cross-resistant to gangciclovir?
- This is because cidofovir and foscarnet do not need to be phosphorylated by viral kinase like ganciclovir does so mutations will not lead to resistance with these drugs
Since ganciclovir (after activation) also targets viral DNA polymerase, mutations that confer foscarnet resistance can also decrease ganciclovir’s effectiveness, leading to cross-resistance.
Be able to describe how cidofovir is metabolized to form the biologically active species.
After entering the host cell, cidofovir is phosphorylated by host cellular kinases to form cidofovir diphosphate (CDV-DP), its biologically active form.
This step is independent of viral enzymes, making cidofovir effective against drug-resistant viruses.
Oseltamivir, Zanamavir, and peramivir MOA
Neuraminidase inhbitors - bind and prevent genome from being cleaved and released to spread virus
Baloxavir MOA
inhibits viral cap snatching
Ribavirin MOA
Works by starving cells of GTP and inhibiting viral polymerase to slow down the replication
inhibits IMPDH which is a host enzyme and starve the viral enzymes. It also binds to viral RNA polymerase
Grazoprevir, Voxilaprevir, Glecaprevir - NS3/4A inhibitors
- Bind to the active site and form an induced fit which means it can no longer accommodate the viral protease and it cannot cleave the polyprotein to initiate activation
- Resistance occurs in the NS3 active site
Sofosbuvir
- Nucleoside RNA polymerase inhibitor
- Prodrug – 3 phosphatases needed
- BINDS TO NS5B
- Binds to viral polymerase and lower activity as well as incorporate itself in the viral RNA chain and cause chain termination by the 2’ methyl group present on the structure
Dasabuvir
- NON- nucleoside RNA polymerase inhibitor
- Binds and inhibits NS5B but not by binding to the active site it binds to allosteric site and leads to conformational changes that blocks nucleotide incorporation into viral RNA
- Ledipasvir, Elbasvir, Daclatasvir, Velpatasvir, Pibrentasvir - NS5A inhibitors
- NS5A inhibitors – bind tightly to NS5A which inhibits both Viral RNA repolication and assembly or release of viral particles
mutation can happen in the first 100 amino acids
Know the basics of the possibility of HBV reactivation during HCV treatment in patients with a known prior HBV infection.
Black box warning for HCV direct acting antivirals – those on treatment with HCV DAAs without interferons has reported reactivation of HBV
to decrease risk of HBV reactivation screen all patients for evidence of current or prior infection before initiation treatment - monitor those who show evidence of current or prior infection
Tenofovir and Lamivudine - MOA
Incorporated into viral DNA and causes DNA chain termination
