24. Chem - Antivirals I (KO)

Introduction

• Viruses are classified based on nucleic acid type (DNA or RNA), morphology (helical or icosahedral), replication site (cytoplasm or nucleus), coating (enveloped or non-enveloped), serological typing, or infected cell types.
• Viral infections can be prevented through immunization or antiviral chemotherapy.
• Antiviral agents work by preventing early viral uncoating or disrupting viral assembly.

Nucleoside Antimetabolites

• Some agents inhibit enzymes in viral replication, these are called nucleoside antimetabolites.
• Retroviruses (a type of RNA virus) have an RNA-dependent DNA polymerase (reverse transcriptase).
• Dideoxynucleoside triphosphates (like AZT and ddC) are good targets for chemotherapy of retroviruses, preventing viral DNA chain termination.

DNA Virus Inhibitors

• DNA viruses have DNA-dependent RNA polymerase (transcriptases) and DNA polymerases, which can be targeted by antiviral drugs.
• Antiviral drugs targeting herpesviruses block replication via three mechanisms:
  • Interference with precursor nucleotide synthesis at the monophosphate stage.
  • Competitive inhibition of DNA polymerase at the triphosphate stage
  • Incorporation into growing DNA strands, resulting in nonfunctional DNA.
• Acyclovir is an acyclic nucleoside that inhibits viral DNA polymerase, and is phosphorylated by viral thymidine kinase.
• Valacyclovir is a prodrug of acyclovir, enhancing bioavailability.
• Ganciclovir is a ganciclovir analog and is also phosphorylated by viral kinases to a triphosphate form that inhibits DNA polymerase.
• Valganciclovir is ganciclovir's prodrug form, increasing bioavailability.

Oseltamivir Phosphate

• Neuraminidase is essential for influenza virus infectivity. Blocking binding of sialic acid to neuraminidase prevents infection, offering effective antiviral treatment.
• Oseltamivir is a prodrug that acts as a neuraminidase inhibitor, increasing oral efficacy.

Interferon α and PEGylated Interferon α-2a

• Interferon α and its PEGylated form are potent cytokines with antiviral, immunomodulatory, and antiproliferative effects.
• PEGylated interferon α-2a is derivatized with polyethylene glycol (PEG) to improve its stability.

Famciclovir

• It's a prodrug form of penciclovir.
• It is phosphorylated to its active form inside the body, then it acts as a competitive inhibitor of viral DNA polymerase, thus inhibiting DNA elongation.

Adenosine-Related Agents

• Adefovir dipivoxil is a prodrug that inhibits DNA polymerase and viral DNA replication, and is useful to treat HIV.

Tenofovir Disoproxil/Alafenamide

• These are prodrugs to improve oral bioavailability.
• They're reverse transcriptase inhibitors.

Lamivudine

• It is a nucleoside analogue that inhibits reverse transcriptase and is significantly effective against HIV.
• It's a deoxycytidine analog, with a substituted sulfur atom instead of a methylene group on the ribose ring.

Ribavirin

• Exact mechanism is unknown, but it probably affects viral RNA or DNA synthesis.

Telbivudine

• A thymidine analog inhibits reverse transcriptase, affecting viral DNA replication.

Sofosbuvir

• It's a prodrug that, upon activation, inhibits viral nucleotide synthesis.

Simeprevir

• Simeprevir inhibits hepatitis C protease, preventing viral maturation and is a substrate for CYP3A4.