SARS-CoV-2 RNA-dependent RNA polymerase complex (RdRp complex)

The SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) complex is the central engine of the viral replication and transcription machinery (Hillen et al., 2020, Nature). It is primarily composed of the catalytic subunit nsp12, which functions in coordination with accessory proteins nsp7 and nsp8 to enhance its processivity and binding to the RNA template (Gao et al., 2020, Science). This complex is responsible for synthesizing the full-length negative-strand RNA intermediates and the subsequent positive-strand genomic and subgenomic RNAs required for viral progeny (UniProt P0DTD1). Because the RdRp is essential for the viral life cycle and lacks a direct human homolog, it serves as a high-priority target for antiviral therapy (Subissi et al., 2014, Antiviral Res). Drugs like remdesivir and molnupiravir target this complex by mimicking natural nucleotides, leading to the cessation of RNA synthesis or the accumulation of deleterious mutations (Kabinger et al., 2021, Nature Structural & Molecular Biology). Understanding the structural dynamics of this complex is crucial for developing next-generation inhibitors that can overcome emerging viral variants.

Other names

nsp12-nsp7-nsp8 complexRNA-directed RNA polymeraseSARS-CoV-2 replicase complexNon-structural protein 12 complex

Nucleoside and nucleotide analogs act as alternative substrates for the RdRp. Remdesivir acts as a delayed chain terminator, while molnupiravir induces "lethal mutagenesis" by causing an accumulation of transition mutations during viral RNA synthesis (Jayk Bernal et al., 2022, NEJM; Yin et al., 2020, Science).