Influenza A virus (2009 H1N1) polymerase acidic protein (PA) endonuclease (PA endonuclease)

The influenza A virus polymerase acidic (PA) protein endonuclease is a vital enzymatic domain within the viral RNA-dependent RNA polymerase complex (UniProt: P03433; UniProt: C3W5S0). It facilitates the "cap-snatching" mechanism, a process where the virus cleaves the 5' capped ends of host cell mRNAs to use as primers for its own mRNA synthesis (Dias et al., Nature, 2009). This activity is indispensable for viral replication, making the PA endonuclease a high-priority target for antiviral drug development (PubMed: 30393431). Baloxavir marboxil is a first-in-class prodrug that, once converted to its active form baloxavir, binds to the active site of the PA endonuclease and inhibits its function (Heo, Drugs, 2018). This inhibition prevents the virus from initiating transcription, thereby reducing viral load and alleviating symptoms of influenza (NIH: StatPearls). Clinical challenges include the rapid emergence of resistance mutations, particularly at the isoleucine-38 position of the PA subunit, which can significantly decrease the effectiveness of the treatment (Uehara et al., Antiviral Research, 2020).

Other names

PA-NterPolymerase acidic protein N-terminal domainCap-dependent endonucleaseInfluenza A virus RNA-directed RNA polymerase subunit PA2009 H1N1 PA endonucleaseInfluenza A virus (2009 H1N1) PA endonucleaseInfluenza A virus PA protein

Inhibition of the cap-dependent endonuclease activity of the viral RNA polymerase complex, preventing the initiation of viral mRNA synthesis (Heo, Drugs, 2018).