Antiviral Agents Overview
Antiviral agents target virus-specific enzymes including viral polymerases, proteases, and entry mechanisms, exploiting differences from host cell machinery.
## Overview
Viruses are obligate intracellular parasites that hijack host cell machinery for replication. Antiviral drug development is challenging because viruses share many cellular processes with the host. Successful targets are virus-encoded enzymes or proteins sufficiently different from human counterparts to allow selective inhibition.
## Herpesviruses (HSV, VZV, CMV, EBV)
**Acyclovir** is a guanosine analog prodrug activated by viral thymidine kinase (TK). Viral TK phosphorylates acyclovir to acyclovir monophosphate; cellular kinases complete activation to acyclovir triphosphate, which inhibits viral DNA polymerase and terminates chain elongation. Selective activation by viral TK provides selectivity. Used for HSV-1/2 (genital herpes, encephalitis) and VZV (shingles). Resistance occurs via TK mutations.
**Valacyclovir** is the L-valine ester prodrug of acyclovir with dramatically improved bioavailability (54% vs. 15-30% for acyclovir).
**Ganciclovir/valganciclovir**: Extended spectrum to include CMV. Phosphorylated by CMV-encoded UL97 kinase. More toxic than acyclovir: myelosuppression (dose-limiting), teratogenic, carcinogenic potential. Used for CMV retinitis, colitis, pneumonitis in immunocompromised patients.
**Foscarnet**: Inorganic pyrophosphate analog that directly inhibits viral DNA polymerase without requiring cellular activation. Used for acyclovir-resistant HSV and ganciclovir-resistant CMV. Nephrotoxicity and electrolyte disturbances (hypocalcemia, hypomagnesemia, hypophosphatemia) are dose-limiting.
## Influenza
**Oseltamivir (Tamiflu), zanamivir, baloxavir**: Oseltamivir and zanamivir inhibit neuraminidase (sialidase), preventing viral release from infected cells. Effective if started within 48 hours of symptom onset. Baloxavir inhibits cap-dependent endonuclease (PA subunit) — single-dose regimen.
## Hepatitis B and C
**HBV nucleoside analogs** (tenofovir, entecavir): Inhibit HBV reverse transcriptase; suppress viral replication without eradicating cccDNA. Long-term therapy for chronic hepatitis B.
**HCV direct-acting antivirals (DAAs)**: Combinations of NS5A inhibitors (ledipasvir, daclatasvir), NS5B polymerase inhibitors (sofosbuvir — nucleotide), and NS3/4A protease inhibitors (simeprevir). Pangenotypic regimens (sofosbuvir/velpatasvir) achieve >95% SVR (sustained virologic response = cure) in 8-12 weeks.
## Key Takeaways
- Acyclovir is activated selectively by viral thymidine kinase; resistance via TK mutations
- Valacyclovir provides improved bioavailability as an acyclovir prodrug
- Ganciclovir covers CMV but causes myelosuppression; foscarnet is used for resistant strains
- HCV DAA combinations achieve >95% cure rates in 8-12 weeks