Uridylate-specific endoribonuclease (Nsp15) (Nsp15)

Uridylate-specific endoribonuclease, commonly referred to as Nsp15 or NendoU, is a highly conserved manganese-dependent enzyme essential for the life cycle of coronaviruses, including SARS-CoV-2 (UniProt: P0DTD1). It specifically cleaves single-stranded and double-stranded RNA at uridylate sites, a process that is critical for viral replication and the evasion of the host's innate immune system (PubMed: 32355862). By processing viral RNA, Nsp15 prevents the accumulation of double-stranded RNA that would otherwise be detected by host pattern recognition receptors such as MDA5, which triggers a robust interferon response (PubMed: 28270580). Consequently, Nsp15 is a key factor in viral pathogenesis and the suppression of host defenses. Because Nsp15 has no close human homologs, it represents an attractive target for the development of broad-spectrum antiviral drugs (PubMed: 32715644). Small molecule inhibitors, such as the repurposed drug Tipiracil, have been shown to bind to the enzyme's active site, blocking its activity and potentially restoring the host's immune response (PubMed: 32908257). Targeting this enzyme could provide a therapeutic strategy to both reduce viral load and enhance the efficacy of the innate immune system against coronavirus infections.

Other names

NendoUNon-structural protein 15Endoribonuclease Nsp15Nsp15 endoribonuclease

Inhibition of the uridylate-specific endoribonuclease activity, which prevents the cleavage of viral poly-uridine sequences, thereby exposing the virus to host innate immune detection and inhibiting viral replication.