Influenza virus RNA polymerase acidic protein cap-dependent endonuclease domain (PA-CEN)

The Influenza virus RNA polymerase acidic protein (PA) cap-dependent endonuclease domain is a critical component of the heterotrimeric RNA-dependent RNA polymerase (RdRp) complex, which also includes the PB1 and PB2 subunits. This specific N-terminal domain of the PA protein is responsible for the 'cap-snatching' process, a mechanism where the virus cleaves the 5' methylated cap from host cellular pre-mRNAs to use as primers for its own viral mRNA synthesis (UniProt P03433; PubMed: 19194459). Because this process is essential for viral transcription and is highly conserved across influenza A and B strains, it serves as a potent target for antiviral therapy. Baloxavir marboxil, a first-in-class prodrug, targets this domain by chelating the divalent metal ions (Mg2+) in the active site, thereby inhibiting the endonuclease activity and stopping viral replication (FDA Label: Xofluza; PubMed: 30184455). Clinical challenges include the emergence of amino acid substitutions at position 38 of the PA protein, which can significantly reduce drug susceptibility.

Other names

PA endonucleasePA-NterInfluenza PA subunitCap-dependent endonucleaseRNA polymerase acidic protein N-terminal domain

Inhibition of the cap-dependent endonuclease activity within the PA subunit of the viral RNA polymerase complex, which prevents the cleavage of host pre-mRNA and subsequently halts the initiation of viral mRNA synthesis.