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

The Nidovirus RNA-dependent RNA polymerase-associated nucleotidyltransferase (NiRAN) is a highly conserved enzymatic domain located at the N-terminus of the non-structural protein 12 (nsp12) in viruses of the order Nidovirales, including SARS-CoV-2 (Lehmann et al., 2015, Nucleic Acids Res). This domain is essential for viral fitness and functions as a nucleotidyltransferase that mediates the first step of the unconventional 5' RNA capping pathway (Yin et al., 2021, Nat Struct Mol Biol). Specifically, it catalyzes the transfer of a nucleoside monophosphate (NMP) to the N-terminus of the viral protein nsp9, which serves as a primer for further capping steps, or potentially directly to the RNA (Slanina et al., 2021, PNAS). Because the NiRAN domain is unique to nidoviruses and lacks a direct human homolog, it is considered an attractive target for broad-spectrum antiviral therapy (Park et al., 2022, J Med Chem). Compounds such as suramin have been identified as potent inhibitors of the NiRAN domain, effectively blocking viral replication by interfering with the formation of the replication-transcription complex (Yin et al., 2021, Nat Struct Mol Biol). Targeting this domain provides a distinct mechanism of action compared to traditional RdRp inhibitors like remdesivir. The structural conservation of the NiRAN domain across different coronaviruses suggests that inhibitors could have pan-coronavirus activity.

Other names

NiRAN domainnsp12 NiRANRNA-dependent RNA polymerase-associated nucleotidyltransferase

Inhibition of the nucleotidyltransferase activity of the NiRAN domain, which prevents the covalent attachment of NMP to nsp9 or RNA, thereby blocking the viral RNA capping process and halting replication (Yin et al., 2021, Nat Struct Mol Biol).