Vaccines and AntiviralsVaccines and Antivirals

Clinical Use of InterferonClinical Use of Interferon

• Therefore they have been used in the treatment of Therefore they have been used in the treatment of cancers of various types. cancers of various types.

• Alpha interferon has shown some effectiveness in the Alpha interferon has shown some effectiveness in the treatment of Hairy cell leukemia, chronic myelocytic treatment of Hairy cell leukemia, chronic myelocytic leukemias, and some T-cell lymphomas.leukemias, and some T-cell lymphomas.

• Unfortunately, the high doses required have many Unfortunately, the high doses required have many serious toxic side effects.serious toxic side effects.

• Combination therapy using interferon as one of the Combination therapy using interferon as one of the components appears promising.components appears promising.

Treatment of Viral InfectionsTreatment of Viral Infections

• What other drugs do we have to fight What other drugs do we have to fight viral infections?viral infections?– Selective toxicity is a problem – the Selective toxicity is a problem – the

antiviral drug must be toxic to the virus antiviral drug must be toxic to the virus without harming the host. This is a without harming the host. This is a problem since viruses rely on their host problem since viruses rely on their host cells for most of the components used in cells for most of the components used in the expression and replication of their the expression and replication of their genomes.genomes.

Antiviral TherapyAntiviral Therapy

– Nucleoside analogues – they target the Nucleoside analogues – they target the viral enzymes (thymidine kinase, DNA viral enzymes (thymidine kinase, DNA polymerase, reverse transcriptase) that polymerase, reverse transcriptase) that are involved in the synthesis of viral are involved in the synthesis of viral DNA. They act as chain terminators. DNA. They act as chain terminators. Selective toxicity is based on the Selective toxicity is based on the differences in the ability of the analogue differences in the ability of the analogue to bind and be utilized by the enzymes to bind and be utilized by the enzymes used in viral DNA synthesis versus those used in viral DNA synthesis versus those used in host cell DNA synthesis.used in host cell DNA synthesis.

Nucleoside AnaloguesNucleoside Analogues

Antiviral TherapyAntiviral Therapy– Amantadine and rimantadine – they block the Amantadine and rimantadine – they block the uncoatinguncoating

step in the viral life cycle of influenza A virus by step in the viral life cycle of influenza A virus by interacting with the M2 proteininteracting with the M2 protein, a porin-like molecule. , a porin-like molecule.

– By binding to M2, the drugs block membrane ion By binding to M2, the drugs block membrane ion channels involved in lowering of the pH in the channels involved in lowering of the pH in the endosomal compartment. endosomal compartment.

– Without the lowered pH, the pH induced conformational Without the lowered pH, the pH induced conformational change that normally releases the fusion peptide of HA change that normally releases the fusion peptide of HA from being buried in the HA trimer does not occur. from being buried in the HA trimer does not occur.

– Therefore, fusion of the viral envelope with the Therefore, fusion of the viral envelope with the endosomal membrane (uncoating) to release the endosomal membrane (uncoating) to release the nucleocapsid into the cytoplasm does not occur.nucleocapsid into the cytoplasm does not occur.

Amantadine and Amantadine and RimantadineRimantadine

Antiviral TherapyAntiviral Therapy

– Zanamavir is a competitive inhibitor of the Zanamavir is a competitive inhibitor of the influenza virus neuraminidase (NA). influenza virus neuraminidase (NA).

– After budding, the virus will normally remain After budding, the virus will normally remain attached to the host cell via the interaction of attached to the host cell via the interaction of the hemagglutinin (HA) ligand with the sialic the hemagglutinin (HA) ligand with the sialic acid receptor on the cell surface. acid receptor on the cell surface.

– The NA will normally cleave the sialic acid to The NA will normally cleave the sialic acid to release the newly made virions. release the newly made virions.

– When this is blocked by zanamivir, the virus When this is blocked by zanamivir, the virus remains tethered to the cell surface and remains tethered to the cell surface and cannot infect new cells. cannot infect new cells.

Zanamivir activityZanamivir activity

Antiviral TherapyAntiviral Therapy

– Protease inhibitors block specific Protease inhibitors block specific proteolytic cleavage of viral proteins. proteolytic cleavage of viral proteins.

– The inhibitors mimic the structure of the The inhibitors mimic the structure of the amino acids near the cleavage site and amino acids near the cleavage site and so they compete, with the normal so they compete, with the normal substrate, for the enzyme.substrate, for the enzyme.

Protease InhibitersProtease Inhibiters

Protease InhibitersProtease 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 TherapyAntiviral Therapy

– Antisense therapy – the mechanism of Antisense therapy – the mechanism of action is similar to that of hybrid action is similar to that of hybrid arrested translation. arrested translation. •A single stranded RNA or DNA moles that is A single stranded RNA or DNA moles that is

complementary to a viral mRNA is made. complementary to a viral mRNA is made.

• It will combine, by complementary base-It will combine, by complementary base-pairing, with the mRNA to block translation pairing, with the mRNA to block translation of the mRNA into a protein productof the mRNA into a protein product

•Hence an essential viral protein is not madeHence an essential viral protein is not made

Antiviral TherapyAntiviral Therapy

– Antisense RNAAntisense RNA

Antiviral TherapyAntiviral Therapy

• si RNA = si RNA = smalling interfering RNAssmalling interfering RNAs..– These are small These are small double stranded RNAsdouble stranded RNAs

that are 21-22 nucleotides in length and that are 21-22 nucleotides in length and that are homologous to an mRNA that that are homologous to an mRNA that you wish to silence (prevent it from you wish to silence (prevent it from being translated).being translated).

– The siRNA complexes with a cellular The siRNA complexes with a cellular endonuclease and the complex will endonuclease and the complex will target homologous mRNA for target homologous mRNA for degradation.degradation.

Action of siRNAAction of siRNA