Anti-Virals 3: Anti-Hepatitis drugs Flashcards
see slides 1 and 2
steps of HBV infection (6)
- Viral entry occurs via liver specific receptors (heparin sulfate proteoglycans)
- Relaxed circular DNA (rcDNA) is converted to closed circular DNA (cccDNA)
- cccDNA undergoes transc to form mRNA and pregenomic RNA (pgRNA)
- pgRNA joins w/ core proteins and P protein to form immature RNA nucelocapsid
- phRNA undergoes reverse transcription to form new partially double stranded DNA (step where polymerase inhibitors work)
- matured enveloped virions released from hepatocyte
steps of HBV polymerase
- HBV polymerase is susceptible to mutation
- High rate = one mutation per 2x105 base mutation
- This is one reason not to use a sole agent in treatment
- HBV polymerase is specialized reverse transcriptase (RT)
- HBV pol uses pgRNA (pregenomic RNA) as the template to make (-)DNA strand
- HBV pol then uses (-)DNA strand to make the (+)DNA strand
- in (-) strand elongation by RT and (+) strand DNA synth, dGMP and dAMP are needed for this step
Drugs against HBV
2 types
Nucloeside/nucleotide analogs – Lamivudine (also for HIV) – Adefovir dipivoxil (also for HIV) – Tenofovir disoproxil (also for HIV) – Tenofovir alafenamide (also for HIV) – Entacavir – Telbivudine – Resistance: M204V/I mutation (2 y) • Interferon drugs
Drugs against HBV
Lamivudine
Phosphorylated by cellular kinases to lamivudine triphos
Inhibits viral DNA pol and RT of HBV
resistance after 4 yrs of treatment
Drugs against HBV
Adefovir
indication
• Against HBV, (HIV, HSV, CMV)
• Phosphorylated by cellular kinases to active diphosphate metabolite (adefovir triphosphate)
- it already has 1 phosphate
– Inhibits HBV DNA pol (RT) as competitive inhibitor – chain termination
- Approved only for chronic HBV infection
- Resistance: N236T mutation (5 y)
Drugs against HBV
Tenofovir
MOA
indication
AE (1)
– dAMP analog – Effect in lamivudine resistant HBV. – Inhibits both protein priming and DNA synthesis – 1st line for chronic HBV • hepatoxicity
Drugs against HBV
Entecavir
MOA
indication
AE (2)
– dGMP analogue
– Gets phosphorylated to the triphosphate
– Inhibits HBV DNA polymerase (RT, +strand synthesis, base priming)
– 1st line for chronic HBV
• Warning: lactic acidosis, hepatotoxicity
Drugs against HBV
• Interferon α (Intron a, roferon a, infergen, alferon n, wellferon)
Interferons (IFNs):
• A family of naturally occurring small proteins and/or glycoproteins
• MW ~ 15 – 28 kDa
• Produced & secreted by cells in response to viral infection
• Induction of cellular enzymes that interfere with viral protein
synthesis
• No oral bioavailability – need to be injected
Drugs against HBV
Interferon - MOA
- inhibit transc+
- activates Mx protein, blocks mRNA syth - inhibit translation
- activates methylase, reduce mRNA cap methylation
- activates 2’5’ oligoadenylate synthetase (inhibits mRNA splicing and activates RNaseL to cleave viral RNA)
- activates protein kinase P1 to inhibit mRNA translation initiation
- activates PDE to block tRNA func - inhibit post-translational processing
- inhibits glycosyltransferase, reducing protein glycosylation - inhibit virus maturation
- - inhibits glycosyltransferase, reducing glycoprotein maturation - inhibit virus release
- causes membrane changes, blocks budding
Drugs against HBV
Interferon - AE (7)
- flu-like symptoms (dissipate ~12 h);
- dose-limiting myelosuppression (granulocytopenia and thrombocytopenia;
- Fatigue and myalagia
- Hearing loss
- Thyroid dysfunction
- Methal confusion & depression.
- contraindicated in pregnancy
Drugs against HBV
Interferon - what to use for HBV? HCV?
- Chronic HBV, acute HCV: IFN
- Chronic HCV: IFN + ribavirin
• PEGylation: improves PK
Drugs against HBV
Ribavirin
what is it?
MOA (2)?
synthetic nucleoside analogue
• Activity: inhibits replication of various DNA and RNA
viruses
Mechanisms (2):
– Interference with viral mRNA elongation (inhibits RNA
pol) in the triphosphate form
– The monophosphate inhibits IMP dehydrogenase, which converts IMP to XMP (needed for GTP synthesis)
Mycophenolic acid
MOA
indications
check hep C virus life cycle
- IMP dehydrog inhibitor
- sig activity against yellow fever
- potentiates inhibitory fx of acyclic guanosine analogues (acyclovir, penciclovir, ganciclovir) against HSV, VSV, CMV
Novel targets for hepatitis C
NS2, NS3/4A
- Peptidases (protease) that process HCV proteins
- Required to cleave the polyprotein into virus structural components.
- Inhibition prevents cleavage of polyprotein chain and halts viral replication
-NS5A – viral replication and assembly
early drugs of protease inhibition
reversible covalent inhibitors
Protease inhibition is considered an important target
- Early drugs demonstrated toxicity and have been withdrawn:
- VictrelisTM (boceprevir)
- Incivek®
, Incivo® (telaprevir)
Telaprevir
• pruritis (~50%); rash (56%)
• rare but life threatening toxic epidermal necrolysis, SJS
• anemia occured (< boceprevir)
Boceprevir
-Anemia (~50%), Neutropenia (~85%)
S3/4A protease inhibitors
Simeprevir
• Faldaprevir (withdrawn)
• Grazoprevir
• Simeprevir
Inhibits the NS3 protease
- prevents cleavage of the viral replication
complex (NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B), so viral RNA cannot be synthesized
Sofosbuvir
MOA
• Nucleotide (RNA) polymerase inhibitor
competes with uridine triphosphate for incorporation into HCV RNA by NS5B polymerase.
Also can act as a chain terminator
- NS5B = RNA pol
suffix: NS3/4A serine protease inh
“-previr”
suffix: NS5B RNA-dep. RNA pol.
“-buvir”
suffix: NS5A protein
“-asvir”
Principles behind drug action for HIV
• HIV targets CD4+ T-lymphocytes mainly.
– Leads to immunodeficiency and opportunistic infection
• Because of resistance/mutation, more than one drug is needed.
• Reverse transcriptase (aka RNA-dependent DNA polymerase) is a main, unique target, although multiple sites of action require multiple drugs taken together
HIV Entry inhibitors
Enfuvirtide
MOA
AE (3)
• Fusion inhibitors
• Enfuvirtide (36 aa peptide) à binds to gp41 glycoprotein
– Resistance: mutations in gp41
• (Serious side-effects:
– Pneumonia, infection at site of injection, allergic reaction)
HIV Reverse transcriptase inhibitors
MOA
• Competitive inhibitors of HIV-1 reverse transcriptase
– NRTIs get incorporated into the viral DNA chain
• -> chain termination
• Drug activation steps:
– Intracellular phosphorylation by cellular kinases to triphosphate
HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs)
MOA
drugs?
These drugs are allostertic modulators of RT. – Delavirdine – Efavirenz – Etravirine – Nevirapine – Rilpivirine
HIV protease inhibitors
MOA
drugs?
Targeting the HIV protease leads to preventing the formation of mature/functional viral proteins, needed for making viral progeny (virions)
• Drug Activation: not required (i.e., no phosphorylation, etc).
– Atazanavir (dysrhythmia, SJS, liver tox)
– Darunavir (liver toxicity, SJS, diabetes)
– Fosamprenavir
– Indinavir (hemolytic anemia, kidney and liver tox).
– Lopinavir (pancreatitis)
– Nelfinavir (liver toxicity)
– Ritonavir (pancreatitis, dysrhythmias, hypersensitivitiy, liver toxicity)
– Saquinavir (dysrhythmias, liver toxicity)
– Tipranavir (hepatotoxicity, intracranial hemorrhage)
HIV Entry inhibitors
Maraviroc
MOA
AE?
CD4 and chemokine (CCR5/CXCR4) receptors facilitate viral entry
- MARAVIROC - binds to host C-C chemokine receptor 5 (CCR5) specifically; so useful for CCR%-tropic-HIV-1
- resistance can develop from mutation in gp120
- severe ADRs: hepatotox, SJS, TEN, cardio impairment
see slide 35 (life cycle of hiv)
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