Influenza virus polymerase acidic N-terminal endonuclease domain (PA-Nter) (PA-Nter)

The Influenza virus polymerase acidic N-terminal endonuclease domain (PA-Nter) is a vital enzymatic component of the heterotrimeric RNA-dependent RNA polymerase (RdRp) complex found in influenza A and B viruses [2, 8, 13]. Its primary biological function is to execute "cap-snatching," a process where the enzyme cleaves the 5'-capped ends of host cellular pre-mRNAs to provide primers for viral mRNA synthesis [3, 9, 19]. This activity is indispensable for viral transcription and subsequent replication within the host cell [10, 14, 18]. In the context of disease, the PA-Nter domain is a key driver of influenza infection, enabling the virus to hijack host machinery and suppress host gene expression through its involvement in the PA-X protein's shutoff activity [13, 17]. As a therapeutic target, it is inhibited by drugs like Baloxavir marboxil, which binds to the domain's active site and chelates essential divalent metal ions [2, 4, 5]. This inhibition effectively halts the production of viral proteins and stops the spread of the infection [6, 21]. However, the clinical utility of such drugs is threatened by the emergence of specific amino acid substitutions, most notably the I38T mutation, which confers resistance by reducing drug binding affinity [6, 11, 16].

Other names

PANPA-NterPA endonucleaseCap-dependent endonucleasePolymerase acidic protein N-terminal domainInfluenza PA-Nter

Inhibition of cap-dependent endonuclease activity by chelating divalent metal ions (Mg2+ or Mn2+) in the active site, which prevents the cleavage of host mRNA caps (cap-snatching) and halts viral mRNA transcription [2, 4, 8, 14].