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

The SARS-CoV-2 RNA-directed RNA polymerase (RdRp), primarily composed of the non-structural protein 12 (nsp12), is the core component of the viral replication-transcription complex (RTC) (UniProt: P0DTD1). It is responsible for synthesizing the viral RNA genome and subgenomic mRNAs, making it indispensable for the viral life cycle (PubMed: 32277040). RdRp operates by utilizing an RNA template to catalyze the phosphodiester bond formation between ribonucleotides, a process significantly enhanced by its interaction with accessory proteins nsp7 and nsp8 (Nature: 10.1038/s41586-020-2168-z). As a viral enzyme with no close human homolog, it is a primary target for broad-spectrum antiviral drugs (NIH: COVID-19 Treatment Guidelines). Therapeutic agents such as remdesivir function as adenosine analogs that cause delayed chain termination during RNA synthesis (Science: 10.1126/science.abc1560). Alternatively, molnupiravir acts as a mutagenic ribonucleoside analog that leads to viral error catastrophe by inducing an unsustainable number of mutations in the viral genome (Nature Structural & Molecular Biology: 10.1038/s41594-021-00651-0). While highly effective, the clinical use of RdRp inhibitors must account for the potential emergence of resistance mutations and specific safety profiles, such as the mutagenic potential of certain analogs in host cells (PubMed: 34469755).

Other names

nsp12Non-structural protein 12RNA-dependent RNA polymerasePolSARS-CoV-2 RdRp

Inhibition of viral RNA synthesis through delayed chain termination or induction of lethal mutagenesis via nucleoside analog incorporation (Science: 10.1126/science.abc1560; Nature: 10.1038/s41594-021-00651-0).