Polymerase acidic protein cap-dependent endonuclease (PA endonuclease)

The polymerase acidic (PA) cap-dependent endonuclease is a critical enzymatic domain located in the N-terminal region of the PA subunit of the influenza virus RNA-dependent RNA polymerase (RdRp) complex (UniProt: P03433) [1]. It plays a central role in the "cap-snatching" process, where it cleaves the 5'-capped headers from host pre-mRNAs to use as primers for viral mRNA synthesis (PubMed: 30604750) [2]. Because this endonuclease activity is essential for viral replication and has no human functional analog, it is a highly specific target for antiviral intervention (NCBI: NBK541078) [3]. Baloxavir marboxil is a first-in-class small-molecule inhibitor that binds to the active site of the PA endonuclease, coordinated by two divalent metal ions, thereby blocking viral transcription (FDA: Xofluza Label) [4]. While effective against both Influenza A and B, the therapeutic utility of targeting this enzyme is challenged by the emergence of resistance mutations, most notably the I38T substitution in the PA subunit (PubMed: 30332983) [5].

Other names

PA-NterInfluenza virus polymerase acidic subunit endonucleaseCap-dependent endonucleaseInfluenza A virus PA protein

Inhibition of the cap-dependent endonuclease activity of the influenza virus polymerase acidic (PA) protein, which prevents the cleavage of host pre-mRNA and subsequent viral mRNA synthesis.