RNA-dependent RNA polymerase complex (RdRp)

The RNA-dependent RNA polymerase (RdRp) complex is the central enzymatic machinery responsible for the replication and transcription of the genome in RNA viruses, including SARS-CoV-2, Hepatitis C, and Influenza (Hillen et al., 2020, Science). This complex typically consists of a core catalytic subunit, such as nsp12 in coronaviruses or NS5B in the Hepatitis C virus, which associates with viral cofactors and the replicated viral RNA terminus to ensure processive and accurate RNA synthesis (Yin et al., 2020, Science; UniProt P0C6X7). Because RdRp is essential for the viral life cycle and lacks a direct functional homolog in human cells, it serves as a highly selective and primary target for antiviral drug development (PubChem). Therapeutic agents targeting this complex, primarily nucleotide analogs like Remdesivir and Sofosbuvir, act by competing with natural nucleotides for incorporation into the nascent RNA strand, leading to premature chain termination or lethal mutagenesis (NIH, 2023; Kabinger et al., 2021, Nature Structural & Molecular Biology). The high degree of structural conservation in the RdRp active site across diverse viral families makes it an ideal candidate for broad-spectrum antiviral strategies against emerging infectious diseases.

Other names

RNA-directed RNA polymeraseViral RNA polymeraseReplicase complexRdRp-RNA initiation complexnsp12-nsp7-nsp8 complexNS5B polymeraseReplicated viral RNA terminus / RdRp–RNA complex

Nucleoside and nucleotide analogs (NAs) act as alternative substrates that are incorporated into the growing RNA chain by the RdRp, resulting in immediate or delayed chain termination or the accumulation of deleterious mutations (lethal mutagenesis) (Kabinger et al., 2021, Nature Structural & Molecular Biology). Non-nucleoside inhibitors (NNIs) bind to allosteric sites on the polymerase to prevent the conformational changes required for catalytic activity (PubChem).