nsp15

Nsp15, also known as nonstructural protein 15, is an RNA uridylate-specific endoribonuclease encoded by coronaviruses as part of the large replicase polyprotein. It is processed from the polyprotein by viral proteases and functions within the replication-transcription complex in the cytoplasm. The protein belongs to the EndoU family and cleaves RNA at uridine residues, contributing to RNA metabolism during replication.

Biochemical properties include dependence on divalent metal ions, commonly manganese (Mn2+), and specificity for uridine-containing substrates. Nsp15 cleaves the phosphodiester backbone after uridines to generate products with 2’,3’-cyclic phosphate and 5’-hydroxyl ends. It assembles as a hexamer, a quaternary structure that is important for catalytic activity. The active-site region contains conserved histidine and lysine residues that participate in catalysis.

Role in infection involves processing of viral RNA species and a proposed function in immune evasion. By cleaving double-stranded or structured RNA that could be recognized by host sensors such as MDA5, Nsp15 is thought to reduce innate immune activation and facilitate efficient replication. In several coronaviruses, disruption of Nsp15 attenuates replication fitness or virulence, indicating a contributing but not universally essential role for replication in cell culture.

Structure and drug discovery efforts have revealed the hexameric assembly and active-site organization, aiding rational inhibitor design. Because of its conserved nature and involvement in immune evasion, Nsp15 is considered a potential antiviral target, with various in vitro inhibitors reported and ongoing research aimed at translating these findings into therapeutic approaches.