Nucleoside/nucleotide analogs are activated by stepwise phosphorylation (host or viral kinase) → triphosphate → incorporated by viral polymerase → chain termination (no 3'-OH) or fatal mutagenesis. Acyclovir family is selectively phosphorylated by HSV/VZV thymidine kinase (not host kinase) → herpes-specific. Tenofovir is acyclic nucleotide (already monophosphate) → fewer activation steps → HIV/HBV. NRTIs (zidovudine, abacavir, lamivudine, emtricitabine, etc.) terminate HIV RT. Sofosbuvir terminates HCV NS5B. Remdesivir + molnupiravir target the SARS-CoV-2 RdRp (different mechanisms — chain termination vs lethal mutagenesis). Entecavir terminates HBV polymerase. Ganciclovir is the CMV-active acyclovir analog (UL97 phosphorylation step).
Organ Systems
immune-hematologic
Pathway Steps
nucleoside-analog → analog-triphosphate — via stepwise phosphorylation by host or viral kinases — activation step. Nucleoside/nucleotide-analog antivirals are prodrugs: host (and sometimes viral) kinases phosphorylate them to the active triphosphate. This activation requirement can confer selectivity — acyclovir, for example, is activated only in herpes-infected cells by viral thymidine kinase.
analog-triphosphate → viral-rna-dna-chain-termination — via incorporated by viral polymerase → 3′-OH missing → no further elongation. The analog triphosphate is incorporated by the viral polymerase into the growing nucleic acid, halting synthesis (chain termination) or causing lethal mutagenesis. This is the mechanism of acyclovir (HSV), tenofovir (HIV/HBV), sofosbuvir (HCV), and remdesivir (SARS-CoV-2).
Known Modulators
acyclovir (inhibitor) — HSV/VZV DNA polymerase (TK-activated). guanosine analog; HSV thymidine kinase phosphorylates selectively; poor PO F (~20%) — valacyclovir prodrug improves to 55%
valacyclovir (inhibitor) — HSV/VZV DNA polymerase (prodrug → acyclovir). L-valyl ester prodrug; 3-5× acyclovir PO F; same MOA + spectrum as parent
famciclovir (inhibitor) — HSV/VZV DNA polymerase (prodrug → penciclovir). penciclovir prodrug; longer intracellular t½ than acyclovir → tid dosing
ganciclovir (inhibitor) — CMV DNA polymerase (UL97-activated). CMV-active acyclovir analog; bone marrow + nephrotoxicity tail; ophthalmologic gel for CMV retinitis
valganciclovir (inhibitor) — CMV DNA polymerase (prodrug → ganciclovir). L-valyl ester prodrug; F 60% vs ganciclovir 6%; oral CMV prophylaxis in transplant
entecavir (inhibitor) — HBV polymerase + reverse transcriptase. guanosine analog; HBV first-line; very high barrier to resistance; not effective for HIV monotherapy (chooses HBV)
tenofovir disoproxil (inhibitor) — HIV-1 reverse transcriptase + HBV polymerase (acyclic nucleotide). TDF; renal + bone toxicity tail; HBV + HIV co-treatment standard
tenofovir alafenamide (inhibitor) — HIV/HBV reverse transcriptase/polymerase (acyclic nucleotide). TAF; cleaner intracellular activation → lower systemic tenofovir → less renal/bone tail than TDF; HIV + HBV
emtricitabine (inhibitor) — HIV reverse transcriptase (cytidine analog). NRTI; bundled in TDF/TAF combos (Truvada, Descovy) for HIV + PrEP
lamivudine (inhibitor) — HIV reverse transcriptase + HBV polymerase (cytidine analog). older NRTI; first HBV oral; resistance develops on monotherapy
abacavir (inhibitor) — HIV reverse transcriptase (guanosine analog). NRTI; HLA-B*5701 mandatory pre-screen for hypersensitivity (severe reaction risk)