SARS-CoV-2 RNA-dependent RNA polymerase (RdRp)

The SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is the central catalytic component of the viral replication-transcription complex (RTC), responsible for synthesizing the viral RNA genome and subgenomic mRNAs (UniProt, 2020). The complex is primarily composed of the catalytic subunit NSP12, which functions in association with accessory proteins NSP7 and NSP8 to achieve high processivity and template binding (NIH, 2020). As an essential enzyme for the viral life cycle with no direct human homolog, RdRp is a primary target for antiviral interventions. Therapeutic agents such as remdesivir and molnupiravir target this enzyme by acting as nucleoside analogs that disrupt RNA synthesis through chain termination or the induction of catastrophic mutation rates (lethal mutagenesis) (PubMed, 2021). Inhibition of RdRp effectively halts the production of new virions, thereby reducing viral load and the severity of COVID-19 (FDA, 2022). The highly conserved nature of the RdRp active site across coronaviruses also makes it an attractive target for broad-spectrum antiviral development.

Other names

NSP12Non-structural protein 12nsp12-nsp7-nsp8 complexReplication-Transcription ComplexRTCRNA-directed RNA polymeraseSARS-CoV-2 RNA-dependent viral replication processes

Drugs targeting the SARS-CoV-2 RdRp primarily act as nucleoside analog inhibitors. These compounds are metabolized into active triphosphate forms that compete with natural nucleotides for incorporation into the nascent RNA strand. Remdesivir acts as a delayed chain terminator, halting RNA synthesis after the addition of a few subsequent nucleotides (NIH, 2020). Molnupiravir functions by inducing lethal mutagenesis, where its incorporation leads to an accumulation of errors in the viral genome that eventually render the virus non-viable (Nature, 2021). Non-nucleoside inhibitors (NNIs) may also target allosteric sites to inhibit enzyme activity (ACS, 2025).