Influenza A virus polymerase acidic cap-dependent endonuclease (PA endonuclease)

The Influenza A virus polymerase acidic (PA) cap-dependent endonuclease is a vital enzymatic domain located within the N-terminal region of the PA subunit of the viral RNA-dependent RNA polymerase (RdRp) complex [1, 4]. Its primary biological role is to execute 'cap-snatching,' a process where the enzyme cleaves the 5' 7-methylguanosine cap from host cellular pre-mRNAs [4]. These snatched caps are then utilized as primers by the PB1 subunit to initiate the transcription of viral mRNA, a step essential for the virus to hijack the host's translation machinery [1, 3]. Because this endonuclease activity is unique to the influenza virus and has no human functional analog, it serves as an ideal target for antiviral therapy [2, 4]. The drug baloxavir marboxil is a first-in-class inhibitor that binds to the active site of the PA endonuclease, which contains two divalent magnesium ions necessary for catalysis [2, 3]. By blocking this site, the drug prevents viral mRNA synthesis and effectively halts viral replication [3]. However, the clinical utility of such inhibitors can be challenged by the rapid emergence of resistance mutations, most notably at the isoleucine 38 position of the PA protein [2, 3]. This target is distinct from other influenza targets like neuraminidase or M2 ion channels, offering a different mechanism for treating infection [2].

Other names

PA endonucleaseCap-dependent endonucleaseCENPA-NterInfluenza A virus PA protein N-terminal domain

Baloxavir marboxil is a prodrug converted to baloxavir, which acts as a selective inhibitor of the influenza virus polymerase acidic (PA) protein's cap-dependent endonuclease activity [2]. It binds to the N-terminal domain of the PA subunit, chelating the manganese or magnesium ions in the active site, thereby preventing the 'cap-snatching' cleavage of host pre-mRNAs required for viral mRNA synthesis [3, 4].