SARS-CoV-2 non-structural protein 12 RNA-dependent RNA polymerase (nsp12 RdRp)

SARS-CoV-2 non-structural protein 12 (nsp12) is the primary catalytic subunit of the viral replication-transcription complex (RTC), serving as the RNA-dependent RNA polymerase (RdRp) [2, 4, 13]. It is responsible for synthesizing the positive-sense viral genome and the subgenomic mRNAs necessary for the production of structural and accessory proteins [5, 6, 11]. The enzyme contains a C-terminal RdRp domain with a conserved "right-hand" structure and an N-terminal nidovirus-specific nucleotidyltransferase (NiRAN) domain that plays a role in RNA capping and protein-primed initiation [1, 10, 13]. To achieve full enzymatic activity and processivity, nsp12 requires the assembly of a holoenzyme complex with its essential cofactors, nsp7 and nsp8 [4, 13, 15]. Given its critical role in the viral life cycle and the absence of a human homolog, nsp12 is a major target for antiviral drug development [4, 17]. Therapeutic agents like remdesivir and molnupiravir target this enzyme by acting as nucleoside analogs that cause premature chain termination or lethal mutagenesis in the nascent viral RNA [2, 7, 9]. However, the efficacy of these drugs can be challenged by the virus's proofreading exonuclease (nsp14) and the emergence of resistance mutations within the nsp12 sequence [4, 15].

Other names

nsp12RdRpRNA-directed RNA polymeraseSARS-CoV-2 RdRpNon-structural protein 12RNA-dependent RNA polymerase nsp12SARS-CoV-2 RdRp complex

Nucleoside analog-mediated delayed chain termination, lethal mutagenesis, and allosteric inhibition of the polymerase active site.