Influenza virus polymerase acidic protein N-terminal endonuclease domain (PA-Nter)

The Influenza virus polymerase acidic protein N-terminal endonuclease domain (PA-Nter) is a critical component of the heterotrimeric RNA-dependent RNA polymerase (RdRp) complex, which also includes the PB1 and PB2 subunits [UniProt: P03433]. Its primary biological function is cap-snatching, a process where the domain cleaves the 5' methylated cap from host cell pre-mRNAs to serve as primers for viral mRNA synthesis [PubMed: 30304070]. This domain is essential for the replication of both Influenza A and B viruses, making it a potent therapeutic target for treating influenza infections [NCBI: NBK541060]. The active site of PA-Nter is characterized by a conserved motif that coordinates two divalent metal ions, typically magnesium or manganese, which are necessary for its catalytic endonuclease activity [Nature: 10.1038/nature07745]. Baloxavir marboxil, a small-molecule inhibitor, binds to this active site and chelates the metal ions, thereby blocking the cleavage of host mRNA and halting the viral life cycle [FDA: Xofluza Label]. Clinical use of these inhibitors has highlighted the potential for resistance, particularly through the I38T mutation in the PA protein, which reduces the drug's inhibitory potency [Lancet Infectious Diseases: 10.1016/S1473-3099(19)30164-1].

Other names

PA endonucleaseInfluenza PA-Nter domainCap-dependent endonucleasePolymerase acidic protein N-terminal domain

Inhibition of the cap-dependent endonuclease activity by chelating divalent metal ions in the active site, thereby preventing the cleavage of host pre-mRNA and halting viral mRNA synthesis.