Non-structural protein 15 endoribonuclease (Nsp15) (Nsp15)

Non-structural protein 15 endoribonuclease (Nsp15) is a highly conserved enzyme found in coronaviruses, including SARS-CoV-2, where it plays a pivotal role in viral replication and host immune evasion [1, 3]. It belongs to the Nidoviral EndoU (NendoU) family and functions as a hexameric complex to specifically cleave single- and double-stranded RNA at uridylate sites [2, 4, 15]. By degrading viral polyuridine sequences, Nsp15 prevents the accumulation of double-stranded RNA intermediates that would otherwise trigger host innate immune sensors like MDA5 and PKR [4, 8, 10]. This activity effectively suppresses the production of type I interferons, allowing the virus to proliferate undetected during the early stages of infection [3, 11]. Given its essential role in dampening the host's antiviral response and its high degree of conservation across the Nidovirales order, Nsp15 is considered an attractive target for the development of broad-spectrum antiviral therapeutics [1, 9]. Research into Nsp15 inhibitors, including repurposed drugs like tipiracil and novel small molecules, aims to restore the host's ability to detect and clear the viral infection [2, 4, 5]. The protein's unique hexameric structure and specific catalytic mechanism offer opportunities for the design of selective inhibitors that do not affect host ribonucleases [13, 15].

Other names

Nsp15NendoUNidoviral endoribonucleaseUridylate-specific endoribonucleasePoly(U)-specific endoribonucleaseRNA uridylate-specific endoribonuclease

Inhibition of uridylate-specific endoribonuclease activity