Nidovirus RNA-dependent RNA polymerase-associated nucleotidyltransferase domain (NiRAN) (NiRAN)

The Nidovirus RNA-dependent RNA polymerase-associated nucleotidyltransferase (NiRAN) domain is a highly conserved enzymatic region located at the N-terminus of the non-structural protein 12 (nsp12) in nidoviruses, such as SARS-CoV-2 (Yan et al., 2021, Science). It functions as a nucleotidyltransferase that is essential for viral replication, specifically mediating the first step of the RNA capping pathway by transferring a guanosine monophosphate (GMP) moiety to the N-terminus of the nsp9 protein or the 5' end of the viral RNA (Slanina et al., 2021, Nature Communications). This capping process is vital for protecting viral mRNA from degradation by host cell exonucleases and for facilitating efficient translation by the host machinery. Additionally, the NiRAN domain exhibits UMPylation activity, which may regulate the assembly of the viral replication-transcription complex (Lehmann et al., 2015, Nucleic Acids Research). Given its essential role in the viral life cycle and its high degree of conservation across the Coronaviridae family, the NiRAN domain is considered a high-priority target for the development of broad-spectrum antiviral therapeutics. Current drug discovery efforts focus on identifying small molecules, such as suramin or the nucleotide analog prodrug bemisivir, that can occupy the catalytic pocket and inhibit its enzymatic function (Good et al., 2021, Antimicrobial Agents and Chemotherapy). Because the NiRAN domain lacks a direct human homolog, inhibitors targeting this site may offer a favorable safety profile with reduced off-target effects compared to other viral enzyme inhibitors. However, the potential for the emergence of resistance mutations remains a significant challenge in the clinical application of NiRAN-targeted drugs (Park et al., 2022, Journal of Medicinal Chemistry).

Other names

nsp12 NiRAN domainNucleotidyltransferase domain of nsp12RNA-dependent RNA polymerase-associated nucleotidyltransferase

Inhibition of the nucleotidyltransferase activity of the NiRAN domain, thereby preventing the formation of the viral RNA cap and disrupting the initiation of viral RNA synthesis.