Influenza virus cap-dependent endonuclease (CEN)

The influenza virus cap-dependent endonuclease is an enzyme present in the PA subunit of the influenza virus RNA-dependent RNA polymerase (RdRp) complex, which also includes PB1 and PB2 subunits. This endonuclease is essential for the “cap-snatching” process, where it cleaves host pre-mRNAs a few nucleotides downstream from the 5’ cap structure, generating capped RNA fragments that are used as primers for viral mRNA synthesis. The activity resides in the N-terminal domain of the PA subunit (PAN), while cap-binding is mediated by the PB2 subunit. The cap-snatching process allows viral mRNAs to mimic host mRNAs, facilitating their recognition and translation by host ribosomes. Drugs such as baloxavir marboxil target this endonuclease, thereby inhibiting viral replication by preventing the formation of functional viral mRNA. Resistance to such drugs commonly arises through mutations at residue I38 in the PA subunit. The enzyme is a validated antiviral drug target for influenza infection.

Other names

Cap-dependent endonucleaseInfluenza RNA polymerase PA subunit endonuclease domainPAN (PA N-terminal endonuclease)Influenza endonuclease

Inhibition of the cap-dependent endonuclease, preventing cap-snatching and thus halting viral mRNA synthesis and replication