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

The Influenza virus polymerase acidic protein (PA) cap-dependent endonuclease domain is a critical component of the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) complex, which also includes the PB1 and PB2 subunits (UniProt: P03433). This specific N-terminal domain of the PA protein is responsible for the "cap-snatching" mechanism, a process where the virus cleaves the 5' methylated cap from host cellular pre-mRNAs to use as primers for its own viral mRNA synthesis (PubMed: PMC6466463). Because this endonuclease activity is essential for viral replication and is highly conserved across various influenza strains, it serves as a potent therapeutic target. Drugs like baloxavir marboxil specifically bind to the active site of this domain, which contains two divalent metal ions, thereby inhibiting the cleavage of host RNA (PubChem: CID 124081523). By blocking this early step in the viral life cycle, these inhibitors effectively halt the production of viral proteins and the assembly of new virions. Resistance to such treatments can emerge through specific amino acid substitutions in the PA domain, most notably the I38T mutation, which reduces the binding affinity of the inhibitor (PubMed: PMC6663284).

Other names

PA endonucleaseInfluenza PA-N domainCap-dependent endonucleasePolymerase 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-mRNAs and the subsequent priming of viral mRNA synthesis (cap-snatching).