This is an antiviral drug-mechanism module structured as a biological pathway, not a specific disease. Its nodes are successive biological steps of viral genome replication (initiation -> catalytic nucleotide incorporation -> processive elongation -> progeny-genome production), with an adaptive resistance branch; the drug classes that act on each step are described in the node text rather than modelled as separate nodes. Disorder entries reference individual nodes via conforms_to (e.g., "viral_polymerase_inhibition#Nucleotide Selection and Catalytic Incorporation at the Polymerase Active Site"), and a polymerase-targeting treatment points its target_mechanisms edge at the step it inhibits (the catalytic-incorporation node for nucleos(t)ide and non-nucleoside inhibitors, the elongation node for the chain-termination effect). Key conformance / treatment target: "Nucleotide Selection and Catalytic Incorporation at the Polymerase Active Site" — the conserved active site shared by RdRp, RT, and viral DNA polymerase. See projects/ANTIVIRAL.md.
Viral Genome Replication Initiation by the Polymerase
trigger
Genome replication begins when the viral polymerase and its cofactors engage the genome template (and, for the primer-dependent enzymes, a primer) to form the replication complex. This is the committed start of the pathway that produces progeny genomes, and it is virus-family-specific in detail but universal in principle: every virus depends on a dedicated polymerase to copy its nucleic acid, which is precisely why that enzyme is such a general antiviral target.
Downstream
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Nucleotide Selection and Catalytic Incorporation at the Polymerase Active Site
Once the complex is assembled, the polymerase active site selects and incorporates nucleotides to copy the template.
Nucleotide Selection and Catalytic Incorporation at the Polymerase Active Site
therapeutic vulnerability
At the catalytic core the polymerase selects an incoming nucleoside triphosphate complementary to the template and joins it to the growing strand through its nucleotidyltransferase activity. This conserved active site is the central drug target of the pathway, attacked by two strategies. Nucleos(t)ide analogues — administered as monophosphate prodrugs to bypass a rate-limiting first phosphorylation and activated by host kinases to the triphosphate form — compete with the natural nucleotide and are mistakenly incorporated. Non-nucleoside inhibitors instead bind an adjacent allosteric pocket and lock the enzyme in a catalytically inactive conformation without being incorporated; because that pocket is less conserved and more mutation-tolerant than the active site, non-nucleoside agents are more virus-specific and lower-barrier than nucleos(t)ide analogues. This is the canonical conformance and treatment target of the module.
Downstream
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Processive Elongation of the Nascent Genome Strand
Successful incorporation of a natural nucleotide allows the polymerase to translocate and continue copying the template.
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Polymerase Active-Site Resistance Mutation
Error-prone copying generates variants with active-site substitutions that resist nucleotide-analogue incorporation.
Processive Elongation of the Nascent Genome Strand
effector
After each incorporation the polymerase translocates and processively extends the nascent strand until a full-length genome copy is made. This is the step that nucleos(t)ide-analogue chain terminators abort: once the analogue has been incorporated, the strand cannot be extended further — immediately for classic terminators or after a few additional residues for delayed terminators such as remdesivir, a feature that also shields the analogue from viral proofreading exonucleases. The result is premature termination of nascent genome synthesis.
Downstream
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Suppression of Genome Replication and Viral Load
Completed elongation yields progeny genomes; blocking elongation collapses genome output and viral load.
Suppression of Genome Replication and Viral Load
consequence
When the catalytic-incorporation and elongation steps are pharmacologically blocked, production of full-length progeny genomes falls, genome replication is suppressed, and viral load declines — the therapeutic endpoint of polymerase-targeting antivirals (for example, the viral suppression achieved by combination antiretroviral therapy). This is the antiviral consequence of engaging the upstream drug-target steps.
Polymerase Active-Site Resistance Mutation
adaptive escape
Viral polymerases, especially the RdRps and RTs of RNA viruses and retroviruses, are error-prone and lack robust proofreading, so a replicating population exists as a quasispecies swarm. Drug pressure at the catalytic step selects variants carrying active-site substitutions that impair nucleotide-analogue incorporation (e.g. HIV RT M184V, HCV NS5B S282T) or allosteric-site changes that escape non-nucleoside inhibitors. This adaptive branch off the catalytic node explains why polymerase-targeting monotherapy fails against high-mutation-rate viruses, and why durable suppression requires combination regimens or single agents with an intrinsically high genetic barrier (sofosbuvir, dolutegravir-anchored regimens).