Polymerase acidic protein (PA) endonuclease domain (PA or PA~N~ (N-terminal domain))

The influenza A virus RNA polymerase PA endonuclease is a highly conserved enzymatic domain that catalyzes a critical step in viral replication called cap-snatching[3][8]. This domain, located at the N-terminus of the polymerase acidic protein, cleaves 10-15 nucleotide capped oligomers from nascent host messenger RNA transcripts, generating primers that the virus uses to initiate synthesis of its own mRNAs[3][8]. The PA endonuclease forms part of a heterotrimeric RNA-dependent RNA polymerase complex with PB1 and PB2 subunits, functioning within viral ribonucleoproteins in the host cell nucleus[3][7]. Because the PA endonuclease is essential for viral mRNA synthesis and is highly conserved across different influenza virus subtypes, it has emerged as an ideal therapeutic target for broad-spectrum antiviral drugs[2][4]. The FDA-approved drug baloxavir marboxil (Xofluza) represents the first approved therapeutic targeting this enzyme, offering single-dose treatment efficacy[9]. However, resistance mutations—particularly the I38T substitution—have already emerged during clinical use, highlighting the need for next-generation PA endonuclease inhibitors that can overcome drug resistance while maintaining activity against diverse influenza strains[2][9].

Other names

Polymerase acidic proteinPA proteinPA~N~ (N-terminal domain designation)P3 (in influenza C virus)Influenza virus polymerase acidic subunit

Direct active site inhibition: Inhibitors directly block the PA endonuclease catalytic site, preventing substrate binding and enzymatic activity. Cap-dependent endonuclease inhibition: Blocks the cleavage of host mRNA caps, preventing their use as primers for viral mRNA synthesis. RNA polymerase complex disruption: Some inhibitors may interfere with assembly or function of the PA-PB1-PB2 heterotrimeric polymerase complex. Broad-spectrum activity: Most inhibitors demonstrate efficacy against influenza A, B, and C virus strains, including those resistant to matrix protein 2 inhibitors and neuraminidase inhibitors.