EXAM 4 antivirals Hepatitis + COVID Flashcards
Hepatitis C lifecycle
Receptor mediated binding and endocytosis
Release of viral RNA
Translation of viral RNA to generate HCV polyprotein
Proteolytic processing of HCV polyprotein
Where serine protease inhibitors act
Formation of replication complex
Where NS5A inhibitors act: daclatasivir
viral RNA replication:
NS5B polymerase inhibitor: sofosbuvir
Virion assembly
Ribavarin MOA
Guanosine analog with incomplete purine ring
inhibits inosine monophosphate dehydrogenase to reduce GTP levels
Leads to direct inhibition of viral RNA pol and incorporates into RNA leading to error catastrophe
Ribavarin spectrum
- Flu A and B
- Hep A,B,C
- Herpes
- Measles
- Hantavirus
- Lassa fever virus
HCV protease inhibitors
“previr”
- Grazoprevir
- Voxilapreveir
- Glecaprevir
HCV protease inhibitors MOA
Target HCV protease NS3 and blocks HCV polypeptide
HCV protease inhibitors resistance
Mutations in NS3 active site
Low genetic barrier of resistance
Retain some activity against 1st gen HCV P1
HCV RNA pol inhibitors (NS5B)
“buvir”
sofosbuvir
dasabuvir
Sofosbuvir MOA
nucleoside RNA polymerase inhibitors
Incorporates in viral RNA chain and causes chain termination
Activation: converted to monophosphate by liver enzyme
Triphosphorylated by nucleotide kinases: YMPK and NDPK
Sofosbuvir resistance
mutation in active site S288T
Dasabuvir MOA
non-nucleoside RNA polymerase inhibitor:
NS5B has 5 known binding sites: catalytic and 4 allosteric
Binds to palm 1 site of HCV RNA polymerase
Prevents conformational change
Blocks nucleotide incorporation into viral RNA
HCV NS5A inhibitors
“asvir”
Ledipasvir 1st gen
Elbasvir
Daclatasvir 1st gen
Velpatasvir
Pibrentasvir
HCV NS5A inhibitors MOA
bind tightly to NS5A and inhibits both viral RNA replication and assembly/release of infectious viral particles
HCV NS5A inhibitors resistance
1st gen: single mutations confer high resistance
2nd gen: higher genetic barrier to resistance and retain activity against common substitutions
What is the black box warning for HCV agents
HBV reactivation has occurred in patients co-infected with HCV
fulminant hepatitis, hepatic failure, and death observed with DAAs used w/o interferons to treat HCV
HBV lifecycle
Partially DS-stranded DNA virus
Viral genome replication includes an RNA intermediate that is converted to viral DNA by reverse transcriptase
HBV drugs
anti-retrovirals: tenofovir and lamivudine
others: entacavir
HBV MOA
telbivudin - isomer of thymidine. Incorporates into viral DNA and causes DNA chain termination
Tenofovir disoproxilfumarate:
Prodrug – converted to tenofovir
Acyclic nucleoside phosphate analog of adenosine
Phosphate cannot be cleaved by cellular esterases –> catabolically stable
Drugs to treat SARS-CoV-2
Remdesivir
Nirmatrlvir
Molnupiravir
Remdesivir MOA and spectrum
MOA: prodrug is bio-transformed to a ribonucleotide analog that can inhibit viral RNA polymerase (adenosine analog)
Spectrum: broad
Nirmatrelvir MOA
MOA: inhibitor of SARS-CoV-2 3C-like protease (3CLpro)
3CLpro cleaves polyprotein 1a and 1ab of SARS-CoV-2
Inhibits active site of cysteine residue in 3CLpro no longer can make proteins
Nirmatrelvir spectrum and metabolism
Spectrum: patients with mild-mod COVID 12+ yo within 5 days of symptom onset
Given with ritonavir (which boost levels since it inhibits CYP3A4)
Molnupiravir:
Prodrug of a synthetic nucleoside derivative of N4 hydroxycytidine
polyermerase inhibitor and chain terminator
