Influenza A virus RNA-dependent RNA polymerase PA subunit endonuclease (PA endonuclease)

The Influenza A virus RNA-dependent RNA polymerase PA endonuclease is a critical enzymatic domain located within the N-terminal region of the PA subunit of the viral polymerase complex (UniProt: P03433). Its primary biological role is to execute the "cap-snatching" process, where it cleaves the 5'-capped primers from host cellular pre-mRNAs (PubMed: 19194459). These stolen caps are then used by the viral PB1 subunit to initiate the transcription of viral mRNA, making the endonuclease essential for viral gene expression (PubMed: 29937329). Because this process is unique to the virus and has no direct human homolog, it serves as a highly specific and effective therapeutic target. Baloxavir marboxil is a first-in-class prodrug that inhibits this endonuclease activity, thereby halting viral protein synthesis and reducing viral load (FDA: Xofluza Label). Clinical use of these inhibitors has highlighted the potential for resistance, particularly through the I38T mutation in the PA subunit, which reduces drug sensitivity (PubMed: 30184455). This target is particularly important for treating influenza strains that may be resistant to neuraminidase inhibitors like oseltamivir. Therapeutic success often depends on early administration within the first 48 hours of symptom onset.

Other names

Polymerase acidic protein endonucleasePA-NterInfluenza PA endonucleaseCap-snatching endonuclease

Inhibition of the endonuclease activity of the PA subunit of the viral RNA polymerase complex, which prevents the "cap-snatching" of host pre-mRNA primers required for viral mRNA synthesis (PubMed: 29937329; FDA: Xofluza Label).