SARS-CoV-2 non-structural protein 15 endoribonuclease (NSP15)

SARS-CoV-2 non-structural protein 15 (NSP15) is a highly conserved, uridine-specific endoribonuclease (EndoU) that plays a pivotal role in the viral life cycle by facilitating immune evasion (1, 2). It functions as a hexameric enzyme that cleaves polyuridine sequences at the 5' end of negative-strand viral RNA, effectively shielding the virus from detection by host innate immune sensors such as MDA5, PKR, and OAS/RNase L (4, 6). By preventing the activation of these pathways, NSP15 suppresses the production of type I interferons, allowing for optimal viral replication and pathogenesis (5, 13). Because NSP15 is essential for viral fitness and is conserved across all coronaviruses, it is a high-priority target for the development of broad-spectrum antiviral therapies (7, 9). Several small molecules, including the FDA-approved drug tipiracil and various experimental inhibitors like hexachlorophene and IPA-3, have been identified as potential NSP15 antagonists that work by binding to its catalytic site or disrupting its oligomerization (2, 18, 20).

Other names

NendoUEndoUUridylate-specific endoribonucleaseNon-structural protein 15nsp15

Inhibition of the uridylate-specific endoribonuclease activity, which prevents the virus from degrading viral polyuridine sequences that would otherwise trigger the host's innate immune sensors (e.g., MDA5, PKR), thereby restoring the host's interferon response.