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233 FINAL > Anti-Virals 3: Anti-Hepatitis drugs > Flashcards

Anti-Virals 3: Anti-Hepatitis drugs Flashcards

1
Q

see slides 1 and 2

steps of HBV infection (6)

A
  1. Viral entry occurs via liver specific receptors (heparin sulfate proteoglycans)
  2. Relaxed circular DNA (rcDNA) is converted to closed circular DNA (cccDNA)
  3. cccDNA undergoes transc to form mRNA and pregenomic RNA (pgRNA)
  4. pgRNA joins w/ core proteins and P protein to form immature RNA nucelocapsid
  5. phRNA undergoes reverse transcription to form new partially double stranded DNA (step where polymerase inhibitors work)
  6. matured enveloped virions released from hepatocyte
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2
Q

steps of HBV polymerase

A
  • 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
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3
Q

Drugs against HBV

2 types

A 
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
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4
Q

Drugs against HBV

Lamivudine

A

Phosphorylated by cellular kinases to lamivudine triphos
Inhibits viral DNA pol and RT of HBV

resistance after 4 yrs of treatment

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5
Q

Drugs against HBV

Adefovir
indication

A

• 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)
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6
Q

Drugs against HBV

Tenofovir

MOA
indication
AE (1)

A 
– dAMP analog
– Effect in lamivudine resistant HBV.
– Inhibits both protein priming and DNA synthesis
– 1st line for chronic HBV
• hepatoxicity
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7
Q

Drugs against HBV

Entecavir

MOA
indication
AE (2)

A

– 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

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8
Q

Drugs against HBV

• Interferon α (Intron a, roferon a, infergen, alferon n, wellferon)

A

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

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9
Q

Drugs against HBV

Interferon - MOA

A
  1. inhibit transc+
    - activates Mx protein, blocks mRNA syth
  2. 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
  3. inhibit post-translational processing
    - inhibits glycosyltransferase, reducing protein glycosylation
  4. inhibit virus maturation
    - - inhibits glycosyltransferase, reducing glycoprotein maturation
  5. inhibit virus release
    - causes membrane changes, blocks budding
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10
Q

Drugs against HBV

Interferon - AE (7)

A
  • 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
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11
Q

Drugs against HBV

Interferon - what to use for HBV? HCV?

A
  • Chronic HBV, acute HCV: IFN
  • Chronic HCV: IFN + ribavirin

• PEGylation: improves PK

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12
Q

Drugs against HBV
Ribavirin

what is it?
MOA (2)?

A

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)

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13
Q

Mycophenolic acid
MOA
indications

check hep C virus life cycle

A
  • IMP dehydrog inhibitor
  • sig activity against yellow fever
  • potentiates inhibitory fx of acyclic guanosine analogues (acyclovir, penciclovir, ganciclovir) against HSV, VSV, CMV
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14
Q

Novel targets for hepatitis C

A

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

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15
Q

early drugs of protease inhibition

reversible covalent inhibitors

A

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%)

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16
Q

S3/4A protease inhibitors

A

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

17
Q

Sofosbuvir

MOA

A

• 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
18
Q

suffix: NS3/4A serine protease inh

A

“-previr”

19
Q

suffix: NS5B RNA-dep. RNA pol.

A

“-buvir”

20
Q

suffix: NS5A protein

A

“-asvir”

21
Q

Principles behind drug action for HIV

A

• 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

22
Q

HIV Entry inhibitors

Enfuvirtide
MOA
AE (3)

A

• 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)

23
Q

HIV Reverse transcriptase inhibitors

MOA

A

• 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

24
Q

HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs)

MOA

drugs?

A 
These drugs are allostertic modulators of RT.
– Delavirdine
– Efavirenz
– Etravirine
– Nevirapine
– Rilpivirine
25
Q

HIV protease inhibitors

MOA

drugs?

A

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)

26
Q

HIV Entry inhibitors

Maraviroc
MOA
AE?

A

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
27
Q

see slide 35 (life cycle of hiv)

A

ok

233 FINAL (15 decks)

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