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Antiviral Drugs by i286R30

VIEWS: 32 PAGES: 12

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               Antiviral Drugs
• Limited selective toxicity
  – Viruses mostly use host cell machinery, so very few
    unique targets
  – Most drugs block steps that take place within cells,
    increasing chances for cell toxicity.
• Virucidal vs. virustatic
  – Can you kill something most people don’t say is
    alive?
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    Viruses and biological principles
• Drugs are specific against specific viruses
  – Further restricts number of effective drugs
  – Unlike bacteria, e.g. where all have 70S
    ribosomes
• Viruses have uncertain evolutionary origin
  – Appear to have evolved independently
     • E.g. influenza (RNA) vs. Herpes
  – Competitive exclusionary principle
     • Viruses can’t occupy same niche
     • Even related Herpes viruses are different
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                                                 Animal Virus
                                                  Life Cycle




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     Steps in viral life cycle available as             4

                 drug targets
• Viral attachment to cells/penetration
  – Highly specific interaction, 1st step in infection
  – Ex: Enfuvirtide, anti-HIV drug
     • Blocks folding of gp41 protein, prevents fusion of
       virus with host cell membrane.
• Uncoating of virus
  – For most viruses, nucleic acid must leave the
    capsid for transcription or replication.
  – Ex: Amantadine, anti-flu drug
     Steps in viral life cycle available as            5
                drug targets-2
• Viral DNA/RNA synthesis
  – Enzymes needed for replication of viral nucleic acid
    are either unique targets (reverse transcriptase) or
    more sensitive than host enzymes to drugs.
  – Numerous examples: many are nucleoside analogs
    that are phosphorylated, inhibit enzymes.
• Viral protein synthesis
  – Listed in table, but?? Nothing that might not be
    better grouped elsewhere
  – Can’t inhibit ribosomes w/o killing host cells
     Steps in viral life cycle available as              6
                drug targets-3
• Inhibition of specific enzymes
  – Overlap: many enzymes that viruses bring are for
    nucleic acid synthesis, e.g. reverse transcriptase (rt)
    or RNA-dependent RNA synthetase.
  – Didoxy nucleosides important as rt inhibitors, azido
    group in place of 3’ OH .
  – HIV protease inhibitors: assembly step?
     Steps in viral life cycle available as                 7
                drug targets-4
• Inhibit viral assembly
  – Proteins attach to nucleic acid, to membrane
  – Many viruses bud, taking host membrane w/ viral
    proteins embedded.
  – HIV makes long precursor protein which is then cut
    into functional proteins by HIV protease
     • Protease inhibitors such as saquinavir, ritonavir,
       and indinavir block this step.
                                                   8
             Block viral release
• Oseltamavir and zanamivir:
• Influenza has H and N spikes
  – H for attachment to surface
    glycoproteins.
  – N is neuraminidase which must
    remove terminal sialic acid
    residues from glycoproteins or new
    virions will attach on way out, get
    stuck.
  –Drugs inhibit neuraminidase; don’t stop viral
  replication, but prevent viral spread.
    Steps in viral life cycle available as   9
               drug targets-4
• Stimulate/assist immune system
  – Natural human peptides used as drugs
  – Interferon
     • Inhibit protein synthesis
     • Degrade viral RNA
  – immunoglobulin
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             Pharmacokinetics
• Many available orally
  – Acid stability and good absorption
  – Necessary for long term HIV treatment
• Some so toxic that only topical rx possible
• Compartment trapping: acyclovir
  – Anti-Herpes guanosine analog
  – Enter cells, phosphorylated by viral thymidine
    kinase; further phosphorylated to triphosphate
  – Trapped in cell, accumulates to high effective dose
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                    Toxicity
• More than with antibiotics, related to primary
  mode of attack on virus
  – Numerous drugs inhibit nucleic acid polymerases,
    producing side effects in actively multiplying cells
     • Much like effect of ionizing radiation, causing
       bone marrow damage, loss of blood cells.
• Some toxicity unrelated: Foscarnet
  – Chelates divalent cations
  – Causes hypolcalcemia and hypomagnesemia
     • Results in seizures and cardiac dysrhymias
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                       HIV
• More drugs vs. HIV than any other virus
  – Seriousness of illness, availability of unique targets
  – Reverse Transcriptase
     • Nucleoside analogs act as competitive inhibitors
       and dideoxys prevent chain elongation
     • Non-nucleosides bind at other site, inhibit
  – Protease inhibitors prevent protein processing
  – Fusion inhibitors (subcut inj only)
  – Always given in combination

								
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