Influenza virus polymerase acidic protein cap-dependent endonuclease (PA endonuclease (sometimes referred to as CEN, cap-dependent endonuclease))

The **Influenza virus polymerase acidic protein cap-dependent endonuclease (PA endonuclease)** is a critical enzymatic domain located in the PA subunit of the heterotrimeric influenza virus RNA-dependent RNA polymerase complex (PA, PB1, PB2)[1][7]. Its principal function is to cleave host cellular pre-mRNAs near their 5′ methylated cap structure, "snatching" short, capped RNA primers that are then used by the viral polymerase for the initiation of viral mRNA synthesis; this process is central to influenza virus replication and transcription[1][3][4]. The cap-dependent endonuclease activity is highly conserved among influenza viruses and is an attractive drug target because it mediates a unique viral function absent from human cellular machinery[6][7]. Several potent antivirals (baloxavir marboxil, pimodivir) have been developed targeting the PA endonuclease, though rapid viral mutational adaptation—especially at the drug-binding site—remains a concern for therapeutic durability[6][3]. The PA endonuclease, in concert with PB1 and PB2 subunits, orchestrates the cap-snatching mechanism, a central feature of influenza virus biology and pathogenesis[1][7].

Other names

PA endonucleaseInfluenza virus PA protein endonuclease domainCap-dependent endonuclease (CEN)Viral RNA-dependent RNA polymerase (endonuclease subunit)Part of influenza virus polymerase complex (PB1, PB2, PA)

Inhibition of endonuclease active site via chelation of divalent metal ions (usually magnesium or manganese) Competitive inhibition at the active site, preventing cap-snatching and halting viral RNA transcription Conformational stabilization of inactive polymerase state (for some inhibitors like pimodivir)