Severe acute respiratory syndrome coronavirus 2 nonstructural protein 15 (Nsp15)

SARS-CoV-2 nonstructural protein 15 (Nsp15) is a uridine-specific endoribonuclease that functions as a key virulence factor by suppressing the host innate immune response. The protein forms a hexameric assembly in which the catalytic EndoU domain becomes enzymatically active and cleaves viral RNA at positions 3′ of uridine residues. By degrading viral double-stranded RNA intermediates, Nsp15 prevents activation of the MDA5-dependent interferon pathway, enabling robust viral replication with reduced immune detection. SARS-CoV-2 variants lacking functional Nsp15 show impaired replication and cause milder disease in animals, establishing Nsp15 as a critical determinant of COVID-19 severity. As a promising therapeutic target, Nsp15 inhibitors could restore antiviral innate immunity and reduce viral load, though selective inhibition is required to avoid off-target effects on conserved host endoribonucleases.

Other names

EndoUuridine-specific endoribonucleaseNendoU

Nsp15 inhibitors block the endoribonuclease catalytic activity, leading to accumulation of viral dsRNA, enhanced interferon pathway activation, and suppression of viral replication.