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

The Influenza virus polymerase acidic N-terminal endonuclease domain (PA-Nter) is a vital enzymatic component of the heterotrimeric RNA-dependent RNA polymerase (RdRp) complex, which also includes the PB1 and PB2 subunits (UniProt P03433). Its primary biological role is to execute the 'cap-snatching' process, a mechanism where the domain cleaves 5'-capped leader sequences from host pre-mRNAs to serve as primers for viral mRNA synthesis (PubMed: 30304617). This activity is essential for the transcription of the viral genome and subsequent replication within the host cell. As a therapeutic target, PA-Nter is highly valued due to its conserved nature across various influenza A and B strains (NIH: PMC6366331). The drug baloxavir marboxil, a first-in-class cap-dependent endonuclease inhibitor, targets this domain by chelating the divalent metal ions in its active site, thereby preventing viral mRNA production (FDA: Xofluza Label). While effective, the primary challenge associated with targeting PA-Nter is the emergence of resistance mutations, particularly the I38T substitution, which significantly reduces drug sensitivity (PubMed: 31536913).

Other names

PA endonucleaseInfluenza PA subunit N-terminal domainInfluenza virus polymerase acidic subunit endonucleasePA-NCap-dependent endonuclease

Inhibition of the endonuclease activity within the PA subunit of the viral RNA polymerase complex, which prevents the cleavage of host pre-mRNAs and the subsequent 'cap-snatching' process necessary for viral mRNA synthesis.