- RNA-dependent RNA polymerase (RdRp) is a specialized enzyme that catalyzes the synthesis of RNA from an RNA template. It plays a fundamental role in the replication and transcription of RNA viruses, including many pathogens of significant medical importance such as SARS-CoV-2, influenza virus, poliovirus, and Ebola virus.
- Unlike DNA-dependent RNA polymerases, which transcribe RNA from a DNA template, RdRps are unique in that they operate independently of DNA, allowing RNA viruses to replicate their genomes in host cells that typically lack this enzymatic function.
- RdRp is a hallmark of RNA viruses and is classified as a viral replicase. It is not found in host cells—particularly in higher eukaryotes—which makes it an attractive target for antiviral drug development. The enzyme is essential for both positive-sense (+) and negative-sense (−) single-stranded RNA viruses, as well as for some double-stranded RNA viruses. In +ssRNA viruses like coronaviruses and flaviviruses, RdRp directly synthesizes a complementary negative-strand RNA that serves as a template for new positive strands. In −ssRNA viruses like influenza and rabies virus, RdRp must first transcribe the genome into mRNA to enable protein production before replication can occur.
- Structurally, RdRp typically has a conserved catalytic core that resembles a cupped “right hand” with fingers, palm, and thumb domains—a structural motif also seen in DNA polymerases. The palm domain contains the active site, characterized by conserved motifs (such as motifs A to G), which coordinate metal ions (usually Mg²⁺ or Mn²⁺) necessary for the polymerization reaction. Despite structural conservation, RdRps vary widely in sequence and complexity across different viral families. For example, the RdRp of SARS-CoV-2 is part of a larger replication-transcription complex involving several nonstructural proteins (e.g., NSP12 as the core RdRp, aided by NSP7 and NSP8 for processivity).
- Functionally, RdRp performs de novo RNA synthesis or primer-dependent synthesis, depending on the virus. Some viruses use short RNA primers or host-derived capped primers (as in the case of influenza “cap-snatching”), while others initiate RNA synthesis without a primer. RdRp must replicate the entire viral genome accurately, but the enzyme generally lacks proofreading or error-correcting mechanisms, leading to high mutation rates in RNA viruses. This contributes to rapid viral evolution, immune escape, and challenges in vaccine development.
- Despite this limitation, a few viruses, notably coronaviruses, encode a proofreading exonuclease (nsp14), which increases replication fidelity and allows them to maintain larger genomes. The presence of this additional enzyme is unusual among RNA viruses and is thought to be a key reason why coronaviruses have genome sizes exceeding 30 kilobases—much larger than most RNA viruses.
- Due to its central role in viral replication, RdRp is a prime therapeutic target. Nucleoside analogs, such as remdesivir, favipiravir, and ribavirin, inhibit RdRp by mimicking natural nucleotides and interfering with RNA chain elongation or fidelity. These drugs can be effective but may suffer from resistance mutations or limited efficacy depending on the virus and treatment timing. Ongoing research continues to focus on developing broad-spectrum RdRp inhibitors and understanding the structural biology of these enzymes to guide rational drug design.
