Antiviral Drugs

Classification

Anti-herpes: acyclovir, valacyclovir, famciclovir, ganciclovir, foscarnet, cidofovir. Anti-influenza: oseltamivir, zanamivir(neuraminidase inhibitors) · amantadine, rimantadine(M2 blockers, now obsolete-resistance). Antiretrovirals: NRTIs, NNRTIs, protease inhibitors, integrase inhibitors, entry/fusion inhibitors. Anti-hepatitis: interferons, ribavirin, DAAs(sofosbuvir etc. for HCV), tenofovir/entecavir(HBV).

Anti-Herpes — Mechanism

Acyclovir: THREE-LAYER selectivity — (1) guanosine analogue, monophosphorylated ONLY by viral thymidine kinase(HSV/VZV-infected cells only, absent in uninfected cells) (2) host kinases → active triphosphate → incorporated into viral DNA by viral DNA polymerase → CHAIN TERMINATOR(no 3’-OH) (3) viral DNA polymerase binds triphosphate with MUCH higher affinity than host polymerase. Triple selectivity = why favourable safety despite interfering with DNA synthesis(every cell depends on this).

Valacyclovir: PRODRUG of acyclovir(better oral bioavailability via ester hydrolysis) — same mechanism, less frequent dosing.

Ganciclovir: similar mechanism(viral kinase activation, but CMV-encoded not HSV thymidine kinase) but MORE toxic → restricted to CMV specifically(immunocompromised/transplant) where acyclovir inadequate.

Foscarnet: does NOT require viral kinase activation — directly inhibits viral DNA polymerase(+HIV RT) at pyrophosphate binding site. Activation-INDEPENDENT → useful vs ACYCLOVIR-RESISTANT strains(resistance usually = lost/altered viral thymidine kinase, which foscarnet doesn’t need). Cost: nephrotoxicity+electrolyte disturbance(hypocalcaemia) → restricted to resistant-strain niche.

Anti-Influenza — Mechanism

Neuraminidase inhibitors(oseltamivir, zanamivir): block viral neuraminidase(cleaves sialic acid anchoring new virions to cell surface) → virions clump, can’t disperse/infect new cells → LIMITS SPREAD, doesn’t directly kill infected cells or block entry. Most effective started EARLY(<48h symptom onset) — directly follows from spread-limiting mechanism.

HIV Antiretrovirals — Mechanism

NRTIs(zidovudine, lamivudine, tenofovir, abacavir, emtricitabine): nucleoside analogues, phosphorylated→triphosphate→incorporated by RT→CHAIN TERMINATION(no 3’-OH) — SAME logic as acyclovir, retroviral target. Zidovudine: BONE MARROW SUPPRESSION(anaemia, neutropenia) — mitochondrial DNA polymerase γ inhibition(off-target, structurally related enough to RT) — SAME “off-target mitochondrial toxicity” class as chloramphenicol.

NNRTIs(efavirenz, nevirapine, rilpivirine): bind RT at DISTINCT allosteric site(no activation needed, unlike NRTIs) → direct conformational change inhibits enzyme. Mechanistically distinct route, same functional endpoint as NRTIs.

Protease inhibitors(ritonavir, lopinavir, atazanavir, darunavir): inhibit HIV protease(cleaves polyprotein precursors into functional viral proteins during maturation) → immature NON-INFECTIOUS virions. DISTINCT life-cycle stage(post-integration, assembly/maturation) vs RT inhibitors(early, reverse-transcription). Ritonavir: now used almost exclusively LOW-DOSE as CYP3A4-inhibiting “BOOSTER”(raises/prolongs co-administered PI levels) — distinct from its own full-dose antiviral use. Metabolic SE(dyslipidaemia, insulin resistance, lipodystrophy) = class-wide PI concern.

Integrase strand transfer inhibitors(raltegravir, dolutegravir, bictegravir): block HIV integrase(inserts proviral DNA into host genome) — EVEN EARLIER life-cycle point than PIs, prevents stable genome integration.

Entry/fusion inhibitors: Maraviroc blocks HOST CCR5 co-receptor(HOST-target mechanism, unusual for antivirals — requires confirming CCR5-tropic strain before use, not CXCR4). Enfuvirtide blocks gp41-mediated fusion directly — both act EARLIEST possible point, before cell entry.

Combination ART(typically 3 drugs, ≥2 classes) = standard, IDENTICAL resistance-prevention logic as TB/leprosy — HIV’s HIGH mutation rate(RT lacks proofreading) → single-agent therapy specifically prone to rapid resistance → combination ESSENTIAL not just preferred.

Clinical Relevance

Recurring theme: selectivity through ACTIVATION-DEPENDENCE. Acyclovir, ganciclovir, NRTIs all achieve favourable safety BECAUSE they need a viral(or virally-induced) enzyme to activate → restricts toxic chain-termination to infected cells/active viral replication. Foscarnet’s activation-INDEPENDENT mechanism = deliberate exception, trading away selectivity specifically to overcome resistance that defeats activation-dependent drugs — direct mechanistic trade-off, not isolated exception to memorize.

Classification (by Target Virus/Mechanism)

Anti-herpes: acyclovir, valacyclovir, famciclovir, ganciclovir, foscarnet, cidofovir
Anti-influenza: oseltamivir, zanamivir (neuraminidase inhibitors); amantadine, rimantadine (M2 channel blockers, now largely obsolete due to resistance)
Antiretrovirals (HIV): multiple classes — NRTIs, NNRTIs, protease inhibitors, integrase inhibitors, entry/fusion inhibitors
Anti-hepatitis: interferons, ribavirin, direct-acting antivirals for hepatitis C (sofosbuvir and others), tenofovir/entecavir for hepatitis B

Anti-Herpes Agents — Mechanism

Acyclovir is the clearest teaching example of selective antiviral toxicity in this entire topic, working through a genuinely elegant two-step selectivity mechanism: (1) acyclovir is a guanosine analogue that must first be monophosphorylated by a virus-encoded thymidine kinase — an enzyme present in HSV/VZV-infected cells but not in uninfected human cells, meaning activation occurs only inside infected cells, and (2) the resulting acyclovir monophosphate is then further phosphorylated by host cellular kinases to the active triphosphate form, which is incorporated into viral DNA by viral DNA polymerase, acting as a chain terminator (acyclovir lacks the 3’-hydroxyl group needed for the next nucleotide to attach) — and additionally, viral DNA polymerase binds acyclovir triphosphate with much higher affinity than host DNA polymerase does, a third, independent layer of selectivity. This triple selectivity (infected-cell-only activation, chain termination, and preferential viral enzyme binding) is why acyclovir has a remarkably favourable safety profile despite directly interfering with DNA synthesis, a process every human cell also depends on.

Valacyclovir is simply a prodrug of acyclovir with substantially improved oral bioavailability (via intestinal/hepatic ester hydrolysis back to acyclovir) — same mechanism, same selectivity logic, just better absorbed, allowing less frequent dosing.

Ganciclovir: mechanistically similar to acyclovir (also requires initial phosphorylation, though by a viral kinase encoded by cytomegalovirus rather than HSV’s thymidine kinase) but with meaningfully greater toxicity, restricting its use specifically to CMV infections (particularly in immunocompromised/transplant patients) where acyclovir has inadequate activity — the toxicity/efficacy trade-off between these two closely related drugs is a specific, examined distinction.

Foscarnet: does not require viral kinase activation at all, directly inhibiting viral DNA polymerase (and HIV reverse transcriptase) by binding the pyrophosphate binding site — this activation-independent mechanism is specifically useful against acyclovir-resistant HSV/VZV strains (resistance to acyclovir most commonly arises from loss/alteration of the viral thymidine kinase needed for the first activation step, which foscarnet simply doesn’t need), but comes at the cost of significant nephrotoxicity and electrolyte disturbance (particularly hypocalcaemia), restricting foscarnet to specifically this resistant-strain niche rather than routine use.

Anti-Influenza Agents — Mechanism

Neuraminidase inhibitors (oseltamivir, zanamivir): block viral neuraminidase, the enzyme responsible for cleaving sialic acid residues that would otherwise anchor newly-budded virions to the infected cell surface — without neuraminidase activity, new virions remain clumped at the cell surface, unable to disperse and infect new cells, limiting viral spread rather than directly killing infected cells or blocking initial entry. Most effective when started early (within 48 hours of symptom onset), a specific, frequently-emphasized clinical point directly following from this mechanism (blocking further spread matters most before extensive spread has already occurred).

HIV Antiretroviral Classes — Mechanism

This topic deserves emphasis proportional to its clinical importance and mechanistic richness:

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): zidovudine, lamivudine, tenofovir, abacavir, emtricitabine — nucleoside analogues that, after intracellular phosphorylation to their active triphosphate form, are incorporated into the growing proviral DNA chain by HIV reverse transcriptase and act as chain terminators (lacking the 3’-OH group), the same fundamental logic as acyclovir’s mechanism, applied to a retroviral target instead. Zidovudine’s defining, most classically-examined adverse effect is bone marrow suppression (anaemia, neutropenia — from mitochondrial DNA polymerase γ inhibition, an off-target effect on a human enzyme structurally related enough to reverse transcriptase to be affected, the same class of “off-target mitochondrial toxicity” mechanism already seen with chloramphenicol under Tetracyclines and Chloramphenicol).

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): efavirenz, nevirapine, rilpivirine — bind reverse transcriptase at a distinct, non-substrate allosteric site (not requiring intracellular activation, unlike NRTIs), causing a direct conformational change that inhibits enzyme activity — a mechanistically distinct route to the same functional endpoint (blocked reverse transcription) as NRTIs.

Protease inhibitors: ritonavir, lopinavir, atazanavir, darunavir — inhibit HIV protease, the enzyme responsible for cleaving large polyprotein precursors into individual functional viral proteins as new virions mature — without this cleavage, newly-produced virions remain structurally immature and non-infectious, a genuinely distinct point in the viral life cycle (post-integration, at the assembly/maturation stage) from where reverse transcriptase inhibitors act (early, at the reverse-transcription stage). Ritonavir is now used almost exclusively at low, sub-therapeutic “booster” doses specifically for its potent CYP3A4-inhibiting property, deliberately raising and prolonging the levels of a co-administered, genuinely therapeutic protease inhibitor (a specific, examined pharmacokinetic-enhancement strategy, distinct from ritonavir’s own independent antiviral use at full dose) — metabolic adverse effects (dyslipidaemia, insulin resistance, lipodystrophy — fat redistribution) are a class-wide concern with protease inhibitors generally.

Integrase strand transfer inhibitors: raltegravir, dolutegravir, bictegravir — block HIV integrase, the enzyme inserting reverse-transcribed proviral DNA into the host genome, an even earlier point in the life cycle than protease inhibitors act, preventing productive infection of the cell before viral genetic material ever becomes a stable, integrated part of the host genome.

Entry/fusion inhibitors: maraviroc blocks the host CCR5 co-receptor (required, alongside CD4, for most HIV strains to enter target cells — a host-target rather than viral-target mechanism, genuinely unusual among antivirals, requiring confirmation that a patient’s viral strain actually uses CCR5 rather than the alternative CXCR4 co-receptor before use); enfuvirtide blocks gp41-mediated membrane fusion directly, preventing viral envelope fusion with the host cell membrane — both act at the very earliest possible point in the HIV life cycle, before the virus has even entered the cell.

Combination antiretroviral therapy (typically three drugs from at least two classes) is standard, for the identical resistance-prevention logic already established for tuberculosis and leprosy — HIV’s high mutation rate (from reverse transcriptase’s inherent lack of proofreading activity) makes single-agent therapy for HIV specifically prone to rapid resistance development, making combination therapy not merely preferred but essential.

Clinical Relevance

The recurring theme across this entire topic is selectivity through activation-dependence: acyclovir, ganciclovir, and the NRTIs all achieve favourable safety profiles because they require a viral (or virally-induced) enzyme to become active, restricting their toxic chain-terminating action specifically to infected cells or cells where viral replication machinery is present — foscarnet’s activation-independent mechanism is the deliberate exception, trading away this selectivity specifically to overcome the resistance that most commonly defeats the activation-dependent drugs, a direct mechanistic trade-off worth understanding rather than memorizing as an isolated exception.

Acyclovir’s three-layer selectivity (viral thymidine kinase activation, chain termination, preferential viral polymerase binding) as a stepwise diagram.
HIV life cycle with each antiretroviral class’s point of action marked (entry/fusion → reverse transcription → integration → protease/maturation).