Polymerase acidic protein (PA) endonuclease (PA endonuclease)

The polymerase acidic (PA) endonuclease is a critical enzymatic component of the influenza virus RNA-dependent RNA polymerase (RdRp) complex, which is composed of PA, PB1, and PB2 subunits [UniProt P03433]. Located in the N-terminal domain of the PA protein, this endonuclease is responsible for "cap-snatching," a process where the virus cleaves the 5' methylated cap from host cellular pre-mRNAs to use as primers for its own mRNA synthesis [PubMed: 29934246]. This function is essential for viral replication and is highly conserved across influenza A and B strains, making it an ideal target for antiviral therapy [NIH: PMC6466057]. Baloxavir marboxil is a potent, small-molecule inhibitor that specifically targets this site, effectively blocking viral transcription [FDA: Xofluza Label]. While highly effective, the emergence of resistance mutations, particularly the I38T substitution in the PA subunit, poses a significant challenge to its long-term clinical utility [PubMed: 30673544]. The specificity of this target is enhanced by the lack of a human homolog for the cap-snatching mechanism, which minimizes potential off-target effects in host cells [PubMed: 30334697]. Ongoing research continues to explore next-generation inhibitors that can overcome the resistance profiles observed with current treatments [PubMed: 32164150].

Other names

Influenza virus PA endonucleasePA-NterCap-dependent endonucleaseRNA-directed RNA polymerase subunit PA

Inhibition of the endonuclease activity of the polymerase acidic (PA) protein, preventing the "cap-snatching" process required for viral mRNA synthesis [PubMed: 30334697].