Polymerase acidic protein endonuclease (Influenza virus) (PA endonuclease)

The polymerase acidic protein endonuclease—commonly referred to as the PA endonuclease—is an enzyme domain located in the N-terminal region of the polymerase acidic (PA) subunit, which itself is part of the influenza virus RNA-dependent RNA polymerase complex (also known as FluPol, comprising PA, PB1, and PB2 subunits). This endonuclease is essential for the viral “cap-snatching” mechanism: it cleaves 5′-capped fragments from host cell pre-mRNAs, which are then used as primers for viral mRNA synthesis. The active site of PA endonuclease contains a highly conserved cluster of acidic residues and histidine, coordinating two manganese ions that are essential for its nuclease activity. Targeting the PA endonuclease has become an effective antiviral strategy, exemplified by the clinical approval of baloxavir marboxil, which inhibits this enzyme and blocks the initial step of viral mRNA transcription. However, resistance mutations—especially at position I38—can significantly reduce drug efficacy, emphasizing the need for ongoing surveillance and development of next-generation inhibitors. To date, the PA endonuclease is a well-characterized, clinically-validated antiviral target unique to influenza virus biology and essential for viral replication and pathogenicity.

Other names

Polymerase acidic endonucleasePA endonuclease domainInfluenza cap-dependent endonucleaseInfluenza PA-N endonuclease

Inhibition of cap-dependent endonuclease activity blocks viral mRNA synthesis, thereby preventing viral replication in host cells