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Vaccines and Antivirals
Clinical Use of Interferon
• Therefore they have been used in the treatment of cancers
of various types.
• Alpha interferon has shown some effectiveness in the
treatment of Hairy cell leukemia, chronic myelocytic
leukemias, and some T-cell lymphomas.
• Unfortunately, the high doses required have many serious
toxic side effects.
• Combination therapy using interferon as one of the
components appears promising.
Treatment of Viral Infections
• What other drugs do we have to fight viral
infections?
– Selective toxicity is a problem – the antiviral
drug must be toxic to the virus without
harming the host. This is a problem since
viruses rely on their host cells for most of the
components used in the expression and
replication of their genomes.
Antiviral Therapy
– Nucleoside analogues – they target the viral
enzymes (thymidine kinase, DNA polymerase,
reverse transcriptase) that are involved in the
synthesis of viral DNA. They act as chain
terminators. Selective toxicity is based on the
differences in the ability of the analogue to
bind and be utilized by the enzymes used in
viral DNA synthesis versus those used in host
cell DNA synthesis.
Nucleoside Analogues
Antiviral Therapy
– Amantadine and rimantadine – they block the
uncoating step in the viral life cycle of influenza A
virus by interacting with the M2 protein, a porin-like
molecule.
– By binding to M2, the drugs block membrane ion
channels involved in lowering of the pH in the
endosomal compartment.
– Without the lowered pH, the pH induced
conformational change that normally releases the
fusion peptide of HA from being buried in the HA
trimer does not occur.
– Therefore, fusion of the viral envelope with the
endosomal membrane (uncoating) to release the
nucleocapsid into the cytoplasm does not occur.
Amantadine and Rimantadine
Antiviral Therapy
– Zanamavir is a competitive inhibitor of the influenza
virus neuraminidase (NA).
– After budding, the virus will normally remain attached
to the host cell via the interaction of the
hemagglutinin (HA) ligand with the sialic acid
receptor on the cell surface.
– The NA will normally cleave the sialic acid to release
the newly made virions.
– When this is blocked by zanamivir, the virus remains
tethered to the cell surface and cannot infect new
cells.
Zanamivir activity
Antiviral Therapy
– Protease inhibitors block specific proteolytic
cleavage of viral proteins.
– The inhibitors mimic the structure of the
amino acids near the cleavage site and so
they compete, with the normal substrate, for
the enzyme.
Protease Inhibiters
Protease Inhibiters
This picture shows the HIV protease (purple and green) complexed with the inhibitor (spacefill).
This prevents the substrate from reacting with the protease and thus, the polypeptides are not
cleaved.
Antiviral Therapy
– Antisense therapy – the mechanism of action
is similar to that of hybrid arrested translation.
• A single stranded RNA or DNA moles that is
complementary to a viral mRNA is made.
• It will combine, by complementary base-pairing,
with the mRNA to block translation of the mRNA
into a protein product
• Hence an essential viral protein is not made
Antiviral Therapy
– Antisense RNA
Antiviral Therapy
• si RNA = smalling interfering RNAs.
– These are small double stranded RNAs that
are 21-22 nucleotides in length and that are
homologous to an mRNA that you wish to
silence (prevent it from being translated).
– The siRNA complexes with a cellular
endonuclease and the complex will target
homologous mRNA for degradation.
Action of siRNA