Polymerase acidic protein (PA) (PA)

The Influenza A virus RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex composed of the PB1, PB2, and PA subunits, which is essential for viral genome replication and transcription [5, 15]. The PA subunit contains an N-terminal domain with cap-dependent endonuclease activity, which is responsible for the "cap-snatching" mechanism [2, 6]. In this process, the polymerase binds to host cell pre-mRNAs via the PB2 subunit and cleaves them 10–15 nucleotides from the 5' cap using the PA endonuclease, generating primers for viral mRNA synthesis [5, 14]. Because this activity is vital for the production of viral proteins and the overall life cycle of the virus, the PA endonuclease has become a primary target for antiviral drug development [7, 9]. Baloxavir marboxil is a first-in-class inhibitor that binds to the active site of the PA endonuclease, effectively blocking viral replication [2, 3]. However, the clinical utility of such inhibitors is challenged by the rapid emergence of resistance mutations, most notably the I38T substitution in the PA subunit, which reduces drug binding affinity [5, 9]. This target is highly conserved across various influenza A subtypes, making it an attractive site for broad-spectrum antiviral therapy [9, 17].

Other names

Influenza A virus RNA-dependent RNA polymerase PA subunitPA endonucleasePA-NterP2 subunitCap-dependent endonuclease

Inhibition of the cap-dependent endonuclease activity of the PA subunit, which prevents the cleavage of host pre-mRNAs (cap-snatching) and the subsequent generation of primers for viral mRNA synthesis [2, 5].