- SARS-CoV-2 RNA polymerase, also known as RNA-dependent RNA polymerase (RdRp) or nonstructural protein 12 (nsp12), is a crucial viral enzyme responsible for the replication and transcription of the SARS-CoV-2 RNA genome. As SARS-CoV-2 is a positive-sense single-stranded RNA virus, its replication cycle depends on this enzyme to synthesize both full-length genomic RNA and subgenomic RNAs that are required for producing viral proteins. The RdRp catalyzes the polymerization of ribonucleotides in the 5′ to 3′ direction, using the viral RNA as a template.
- Structurally, the core RdRp is composed of nsp12, which adopts the classical cupped right-hand configuration typical of RNA polymerases, comprising finger, palm, and thumb domains. This configuration is highly conserved among coronaviruses. For full enzymatic activity and enhanced processivity, nsp12 associates with two cofactors: nsp7 and nsp8. These accessory proteins form a complex with nsp12 and are thought to act as a sliding clamp or primase-like elements that stabilize the polymerase on RNA templates, allowing for the efficient synthesis of long RNA strands.
- Functionally, SARS-CoV-2 RdRp carries out two main tasks: the replication of the full-length viral genome and the transcription of subgenomic RNAs through a unique mechanism known as discontinuous transcription. This allows the virus to produce multiple mRNA transcripts from the same RNA genome, each encoding different structural or accessory proteins. The fidelity and regulation of this process are critical for the production of viable viral progeny.
- Due to its central role in the viral life cycle and absence of homologous enzymes in human cells, the RdRp is a major target for antiviral therapies. Nucleoside analogs such as remdesivir and molnupiravir are designed to be incorporated by RdRp into the growing RNA chain. These analogs act by causing premature termination or introducing mutations that hinder further replication, thereby impeding viral propagation. Structural studies, particularly those using cryo-electron microscopy, have provided detailed insights into the RdRp complex, supporting the rational design of new inhibitors.
- In summary, the SARS-CoV-2 RNA polymerase is a multifunctional enzyme critical for viral RNA synthesis and a primary target for therapeutic intervention. Its essential role in viral replication, combined with its structural and mechanistic uniqueness, underscores its importance in the biology and treatment of COVID-19.
