Antiviral drugs Flashcards
Acyclovir
Inhibits nucleic acid synthesis: competitive inhibitor of dGTP causing termination and trapping the DNA polymerase
Requires metabolic activation to triphosphate form (first one is by viral kinase)
Tx: herpes simplex virus 1 & 2, varicella zoster virus, cytomegalovirus
Poor oral bioavailability
Boceprevir
Prevents cleavage of precursor polypeptides of HCV: inhibits Ns3/4A serine protease
Foscarnet
Inhibition of pyrophosphate cleavage (need to cleave pyrophosphate before linking to the previous component and stops replication)
inhibits DNA/RNA pol and RT
Ganciclovir
Inhibits nucleic acid synthesis: competitive inhibitor of dGTP causing termination and trapping the DNA polymerase
Requires metabolic activation to triphosphate form (first one is by viral kinase)
Tx: herpes simplex virus 1 & 2, varicella zoster virus, cytomegalovirus
Poor oral bioavailability
Oseltamivir
Neuraminidase inhibitor: destroy receptors (sialic residues) recognized by viral hemagglutinin on cell surface
decrease in progeny virions
Viral aggregation at cell surface and reduced virus spread within respiratory tract
Prevents release of influenza A and B virus from infected cell
Ribavarin
Inhibits inosine monophosphate dehydorgenase
Inhibits nucleic acid synthesis: competitively inhibits GTP-dependent 5’ capping of viral mRNA and specifically influenza virus transcriptase activity
Multiple sites of interacting action of GTP-dependent enzymatic processes (some of these may potentiate others)
May enhance viral (lethal) mutagenesis
Converted to triphosphate
Trifluridine
Inhibits nucleic acid synthesis: irreversibly inhibits thymidylate synthase and specific DNA pol
Lesser extent: incorporated in cellular DNA in both infected and uninfected cells (decreasing host DNA synthesis)
Resistance is rare
Tx: HSV- induced keratitis and keratoconjunctivitis
Zanamivir
Neuraminidase inhibitor: destroy receptors (sialic residues) recognized by viral hemagglutinin on cell surface
decrease in progeny virions
Viral aggregation at cell surface and reduced virus spread within respiratory tract
Prevents release of influenza A and B virus from infected cell
Amantadine
Binds M2 protein: Ion channel blocker
Inhibits viral uncoating of Influenza A
Peginterferon Alfa
Inhibits protein synthesis directed by viral mRNA
Signals cell to make antiviral proteins: inhibit translation and other steps in viral replication
Rimantadine
Binds M2 protein: Ion channel blocker
Inhibits viral uncoating of Influenza A
Valacyclovir
Prodrug for acyclovir
Better oral bioavailability
Valganciclovir
Prodrug for ganciclovir
Better oral bioavailability
Abacavir
NRTI
Lamivudine
NRTI
Inhibits nucleic acid synthesis by HBV: competitively inhibits HBV DNA pol
Converted to triphosphate form
Tenofovir Disoproxil
NRTI
Already a monophosphate (nucleotide not a nucleoside)
Zidovudine
NRTI
decrease risk of fetal transmission
Emtricitabine
NRTI
Didanosine
NRTI
Stavudine
NRTI
Efavirenz
NNRTI
Nevirapine
NNRTI
Atazanavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
NO CYP3A4 inhibition
Ritonavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
Inhibits CYP3A4
Amprenavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
Indinavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
Lopinavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
Nelfinavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
Saquinavir
HIV-1 aspartyl protease inhibitor: inhibits cleavage of HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus
Enfuvirtide
Fusion inhibitor (traps HIV and host at attachment stage): binds HR1, preventing HR2-HR1 interaction (binds gp41)
Maraviroc
Fusion inhibitor: antagonist of CCR5 chemokine receptor that HIV uses for attachment and entry
Not all HIV strains use this receptor
CYP3A4 and P-gp
Raltegravir
DNA strand transfer inhibitor
Inhibits integrase that integrates HIV DNA into host DNA
Entecavir
Inhibits nucleic acid synthesis by HBV: competitive inhibitor of HBV DNA pol (dGTP)
Converted to triphosphate
Weak inhibitor of cellular DNA and mitochondrial polymerases
Adefovir
Inhibits nucleic acid synthesis by HBV: competitive inhibitor of viral DNA polymerases and RT (dATP)
Converted to diphosphate form
Higher affinity for HBV than host
Telbivudine
Inhibits nucleic acid synthesis by HBV: competitive inhibitor of HBV DNA pol (Thymidine 5”-triphosphate)
Converted to triphosphate form
Little toxicity toward human DNA pol
Telaprevir
Inhibits cleavage of precursor polypeptides of HCV: inhibits Ns3/4A serine protease
NRTI
Nucleoside Reverse Transcriptase Inhibitors: competitive inhibition (bind active site) by competing with endogenous nucleosides for incorporation into viral DNA (indirectly inhibits pol); terminate DNA (lack 3’ OH)
Also inhibit host cell mitochondrial DNA pol: Many significant toxicities (anemia, granulocytopenia, myopathy, peripheral neuropathy, and pancreatitis)
Converted to triphosphate nucleotides by host cell kinases
Resistance: thymidine analog mutations (TAMS); change of target and host repair systems
NO CYP interactions
NNRTI
Non-Nucleoside Reverse Transcriptase Inhibitors: bind to hydrophobic pocket of the p66 subunit of HIV-1 RT; non competitive inhibitors (change dynamic of receptors)
Resistance: mutation in p66 pocket without affecting enzyme activity of virus
Specificity for HIV-1
ALL CYP substrates (all but one inducers or inhibitors)
Do NOT require phosphorylation
Protease inhibitor issue
Protease: Clip precursor into individual proteins
Primary mutation: doesn’t necessarily make resistance
Secondary mutation: need multiple mutations to evade drug
substrates for P-gp energy dependent efflux pump
ALL substrates and inhibitors of CYP3A4
HAART therapy
Start at time of HIV dx
2 NRTI + 1 NNRTI or protease inhibitor or integrase inhibitor
