Polymerase acidic protein endonuclease (PA endonuclease) (PA endonuclease)

The polymerase acidic (PA) protein endonuclease is a vital enzymatic component of the influenza virus RNA-dependent RNA polymerase (RdRp) complex, which is responsible for viral genome replication and transcription (UniProt P03433). The N-terminal domain of the PA subunit contains the active site for endonuclease activity, which is central to the cap-snatching mechanism (PubMed: 30304656). In this process, the enzyme cleaves the 5-capped leader sequences from host cellular pre-mRNAs to use them as primers for viral mRNA synthesis (NIH: PMC6366331). Because this function is essential for viral survival and lacks a direct human homolog, it serves as an ideal target for antiviral therapy. Baloxavir marboxil is a first-in-class drug that selectively inhibits this endonuclease activity, thereby blocking viral replication (FDA: Xofluza Label). This target is effective against both Influenza A and B viruses, providing an alternative to neuraminidase inhibitors like oseltamivir. However, the clinical utility is threatened by the emergence of specific resistance mutations, most notably the I38T substitution in the PA protein (PubMed: 31189110).

Other names

Influenza virus PA endonucleasePA-NterRNA-directed RNA polymerase subunit PAPolymerase acidic protein N-terminal domainCap-dependent endonuclease

Inhibition of the cap-dependent endonuclease activity within the polymerase acidic (PA) subunit of the influenza virus polymerase complex, preventing the cap-snatching process required for viral mRNA synthesis.