Antiviral agents and mechanisms

Viral Lifecycle - Targets of Attack

• Antivirals exploit the viral replication cycle. Key targets are enzymes and processes unique to the virus, minimizing host toxicity.

⭐ Most nucleoside analogs (e.g., Acyclovir, Ganciclovir) are prodrugs that require initial phosphorylation by a viral kinase. This crucial first step ensures selective activation within infected cells.

Nucleic Acid Inhibitors - Forging Fakes

• Mechanism: These drugs are structural analogs of purines or pyrimidines. They are incorporated into growing viral DNA, acting as chain terminators.
• Activation: Most require phosphorylation by a viral kinase (e.g., HSV/VZV thymidine kinase) to become active monophosphates, then by host cell kinases to triphosphates.
  • Acyclovir, Valacyclovir, Ganciclovir.
• Direct Inhibitors: Some bypass this activation.
  • Cidofovir: A nucleotide analog, requires only host kinases.
  • Foscarnet: A pyrophosphate analog, directly inhibits DNA polymerase without any phosphorylation.

⭐ Ganciclovir is notorious for causing dose-dependent myelosuppression (neutropenia, thrombocytopenia), a major toxicity concern, especially in transplant patients.

Protease & Release Inhibitors - Gumming the Works

• Protease Inhibitors (-navir)

  • Mechanism: Inhibit viral proteases (e.g., HIV protease), preventing cleavage of viral polyproteins into mature, functional proteins. This "gums up the works" for viral assembly. 📌 "-navir" never cleaves.
  • Agents: Atazanavir, Darunavir, Ritonavir.
  • Adverse Effects: Lipodystrophy, hyperglycemia, GI intolerance.

  ⭐ Ritonavir is a potent cytochrome P450 inhibitor, often used to "boost" the concentration of other protease inhibitors.

• Neuraminidase Inhibitors (-amivir)

  • Mechanism: Inhibit influenza neuraminidase, blocking the release of newly formed virions from the host cell.
  • Agents: Oseltamivir (oral), Zanamivir (inhaled).
  • Use: Treatment and prevention of Influenza A and B.

Immunomodulators - Sounding the Alarm

• Interferons (IFNs): Host cytokines that induce an "antiviral state." They signal neighboring cells to upregulate enzymes that degrade viral RNA and inhibit protein synthesis, effectively halting viral replication.

  • IFN-α: Used for chronic HBV, HCV, Kaposi sarcoma, and condyloma acuminatum.
  • IFN-β: Primarily for multiple sclerosis.
  • Adverse Effects: Flu-like symptoms, depression, myelosuppression.

• Imiquimod:

  • Mechanism: A Toll-like receptor 7 (TLR7) agonist that upregulates NF-κB, stimulating innate and adaptive immune responses.
  • Use: Topical treatment for anogenital warts (HPV).

⭐ Interferons do not act on the virus directly but on the host cell's machinery to prepare it for defense-a key paracrine signaling mechanism against viral spread.

High‑Yield Points - ⚡ Biggest Takeaways

• Acyclovir and valacyclovir are guanosine analogs requiring viral thymidine kinase for activation, primarily used for HSV/VZV.
• Ganciclovir is the first-line treatment for CMV retinitis but can cause significant myelosuppression.
• Foscarnet directly inhibits DNA polymerase and is used for resistant CMV/HSV, but it is highly nephrotoxic.
• Oseltamivir and zanamivir are neuraminidase inhibitors that prevent the release of new influenza A and B virions.
• NRTIs cause chain termination; a key class toxicity is mitochondrial damage.