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.
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.
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.
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 • 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.