Polymerase basic protein 2 (PB2) (PB2)

The Polymerase basic protein 2 (PB2) is a critical subunit of the heterotrimeric RNA-dependent RNA polymerase (RdRp) complex of the Influenza A virus, working alongside the PB1 and PA subunits (UniProt P03428). Its primary biological function is the cap-snatching mechanism, where it recognizes and binds to the 5' methylated caps of host cellular pre-mRNAs to provide primers for viral mRNA transcription (Stevaert and Naesens, 2016). Beyond its role in replication, PB2 is a major determinant of viral pathogenicity and host adaptation, often interacting with host proteins like MAVS to suppress the innate immune response (Graef et al., 2010). As a therapeutic target, PB2 is highly attractive because its cap-binding domain is essential for the virus and lacks a direct human homolog, allowing for high drug selectivity (Clark et al., 2014). Inhibitors such as Pimodivir (VX-787) and the recently approved Onradivir target the cap-binding pocket of PB2 to halt viral transcription and replication (Trevejo et al., 2018; NMPA China, 2025). These drugs have demonstrated potent activity against various Influenza A strains, including those resistant to neuraminidase inhibitors. However, the clinical utility of PB2 inhibitors is frequently challenged by the rapid emergence of resistance mutations, such as S324C and M431L, which reduce drug binding affinity (Patel et al., 2021). Consequently, ongoing research focuses on developing next-generation inhibitors and combination therapies to overcome these resistance barriers and improve patient outcomes in both seasonal and pandemic influenza infections.

Other names

Influenza A virus polymerase subunit PB2RNA-directed RNA polymerase subunit PB2RNA-directed RNA polymerase subunit P3PB2 proteinPolymerase basic 2

Inhibition of the cap-binding domain (CBD) of PB2, which prevents the binding of host 7-methylguanosine (m7G) caps, thereby blocking the cap-snatching process required for viral mRNA synthesis (Clark et al., 2014; Byrn et al., 2015).