Transcript Antiviral Drugs

Antiviral Drugs
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• 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?
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
drug targets
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• 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
drug targets-2
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• 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
drug targets-3
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• 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
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.
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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.
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Steps in viral life cycle available as
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
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• 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
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
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• 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