RNA-Dependent RNA Polymerase Mechanisms in Viral Infections

RNA-dependent RNA polymerases (RdRps) are central to the life cycle of RNA viruses, orchestrating both genome replication and transcription. These enzymes bear a conserved cupped right-hand architecture comprising fingers, palm and thumb domains that bind RNA templates and catalyse phosphodiester bond formation. RdRps often associate with viral co-factors to form multi-subunit complexes, enhancing processivity and fidelity. Despite a conserved catalytic core, individual RdRps differ in accessory domains, error rates and interactions with host factors. High-resolution structural studies have revealed how nucleoside analogues and non-nucleoside inhibitors engage the polymerase active site or RNA binding channels to stall chain elongation or induce lethal mutagenesis. Host proteins such as interferon-induced enzymes can synthesise nucleotide derivatives that directly inhibit RdRp activity, representing an intrinsic antiviral defence. Emerging insights into the dynamics of template-primer binding, translocation barriers and proofreading by viral exonucleases underpin rational drug design, with implications for broad-spectrum antivirals. Advances in cryo-electron microscopy and synthetic RNA chemistry continue to expose mechanistic details of nucleotide incorporation, translocation stalling and error propagation, highlighting RdRp as an Achilles heel of RNA viruses with significant implications for pandemic preparedness and therapeutic intervention.

Research from Nature Portfolio

Recent structural elucidation of the SARS-CoV nsp12 polymerase bound to its nsp7 and nsp8 co-factors uncovered a kinase-like N-terminal extension and a conserved polymerase core, offering a template for antiviral design and clarifying the assembly of the coronavirus replication machinery. Mechanistic studies of remdesivir have employed cryo-EM and synthetic RNA to demonstrate that incorporation of the analogue permits three additional nucleotides before a translocation barrier at the polymerase active site stalls elongation, concurrently hindering viral proofreading. Investigations of favipiravir reveal that the highly active coronavirus RdRp complex incorporates the nucleoside analogue with unprecedented speed and error rate, provoking lethal mutagenesis through transitions in the viral genome and pinpointing polymerase permissiveness as a vulnerability for therapeutic development.

RNA-Dependent RNA Polymerase Mechanisms in Viral Infections publication trend

The graph below shows the total number of articles in rna-dependent rna polymerase mechanisms in viral infections across all publications each year (not limited to Nature Index journals).

Technical terms

RNA-dependent RNA polymerase (RdRp): Enzyme that synthesises RNA from an RNA template, essential for replication of RNA viruses.

Cryo-electron microscopy: Imaging technique that determines biomolecular structures at near-atomic resolution by rapidly freezing samples.

Co-factors (nsp7, nsp8): Auxiliary viral proteins that associate with RdRp to enhance its processivity and structural stability.

Nucleoside analogue: Molecule resembling natural nucleotides, incorporated into viral RNA to terminate or distort replication.

Non-nucleoside inhibitor: Small molecule that binds to regions outside the active site, altering polymerase conformation to prevent RNA synthesis.

Translocation barrier: Obstruction to the movement of RdRp along the RNA template, leading to stalling of chain elongation.

Lethal mutagenesis: Accumulation of mutations in the viral genome due to error-prone replication, resulting in loss of infectivity.

References

1. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nature Communications (2019).
2. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nature Communications (2021).
3. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nature Communications (2020).
4. CMPK2 is a host restriction factor that inhibits infection of multiple coronaviruses in a cell-intrinsic manner. PLOS Biology (2023).
5. Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr. Proceedings of the National Academy of Sciences of the United States of America (2025).
6. Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP. Proceedings of the National Academy of Sciences of the United States of America (2021).