Influenza A virus RNA-directed RNA polymerase subunit PB2 (PB2) (PB2)

Influenza A virus RNA-directed RNA polymerase subunit PB2 is a critical component of the heterotrimeric viral polymerase complex, which also includes PB1 and PA subunits [4, 11]. PB2 is primarily responsible for the "cap-snatching" mechanism, where it binds to the 5' methylated cap of host cellular pre-mRNAs to provide primers for viral mRNA transcription [1, 13]. Beyond its role in replication, PB2 is a major determinant of viral host range and virulence; human-adapted strains often feature specific mutations (e.g., E627K) and mitochondrial localization that allow the virus to suppress host innate immune responses by interacting with the mitochondrial antiviral signaling (MAVS) protein [2, 8]. Because PB2 is essential for the viral life cycle and lacks a direct human homolog, it is a high-priority target for antiviral development [4, 10]. Pimodivir (VX-787) is a first-in-class inhibitor that targets the PB2 cap-binding pocket, effectively blocking viral transcription [5, 6]. However, the clinical utility of PB2 inhibitors is challenged by the rapid emergence of resistance mutations, such as S324N and F404Y, which necessitate ongoing monitoring and the potential for combination therapies [5, 7].

Other names

Polymerase basic protein 2PB2 subunitRNA-directed RNA polymerase catalytic subunit PB2P2 proteinPB2

Pimodivir acts as a competitive inhibitor of the PB2 cap-binding domain, preventing the binding of host 7-methylguanosine (m7G) capped mRNA, which is essential for the initiation of viral mRNA transcription via the cap-snatching mechanism [1, 5, 11].