ANTIVIRAL CHEMOTHERAPY

• AMANTADINE and RIMANTADINE:

  • ACTION: Inhibits the uncoating stage (part of binding) of Influenza A virus.

    • Binds to M-Protein and blocks the pre-lysosomal uncoating, after attachment has already taken place.

    • Viruses can acquire resistance with extended use.

  • VIRUSES: Inhibits primarily the Influenza A virus, but also has activity against Influenza C, Sendai, Dengue, and Rubella viruses.

    • Parainfluenza 1,2,3, Influenza B, and RSV are resistant

  • SIDE-EFFECTS: In 10% of patients, CNS toxicity, nervousness, difficulty concentrating.

  • CLINICAL: Use is restricted to certain subgroups: in epidemics, at-risk patients, hospitalized patients.

• RIBAVIRIN:

  • ACTION: Inhibits viral transcription, by binding to and inhibiting enzymes involved in nucleic acid metabolism. Specifically inhibits inosine monodehydrogenase, involved in the synthesis of GTP.

  • SIDE-EFFECTS: It is toxic in that it does not discriminate well between host cell and virus. Toxic to liver cells and can cause anemia.

  • VIRUSES: RSV in infants, and Lassa Fever intravenously.

• ACYCLOVIR:

  • ACTION: It is converted by HSV viral Thymidine Kinase into a monophosphate activated form. Host cell then converts monophosphate form into triphosphate form. This form then does two things:

    • Binds and inhibits viral DNA polymerase

    • It is incorporated into viral DNA, where it acts as a chain-terminator.

  • RESISTANCE in HSV is due to mutations in two different viral proteins:

    • Viral Thymidine Kinase, preventing conversion of acyclovir to the triphosphate form.

    • Viral DNA polymerase, such that it doesn't bind the drug.

  • VIRUSES: Specific for HSV infections: HSV-1, HSV-2, VZV, but not CMV or EBV.

    • Resistance can occur, due to mutations in either Thymidine Kinase or viral DNA polymerase.

• ADENINE ARABINOSIDE (Ara A):

  • ACTION: Binds to DNA-Polymerase -- cellular or viral, thus bad side effects.

  • VIRUSES: Used to be used for HSV-Encephalitis cases. Now surpassed by Acyclovir.

• GANCICLOVIR:

  • VIRUS: CMV, promising new treatment. Also works on HSV.

    • Up to 80% of HIV patients will relapse if therapy is discontinued. CMV pneumonia does not respond as well as other CMV infections.

  • ACTION: Nucleoside analog of guanosine, similar to Acyclovir.

  • SIDE-EFFECTS: Reversible neutropenia, liver and CNS toxicity.

• AZIDOTHYMIDINE (AZT, ZIDOVUDINE):

  • ACTION: Inhibits Reverse Transcriptase.

    • AZT is phosphorylated first by host enzymes.

  • VIRUS: HIV-1

Category: Microbiology Notes