Influenza A virus RNA-directed RNA polymerase (RdRp) (RdRp)

The Influenza A virus RNA-directed RNA polymerase (RdRp) is a heterotrimeric enzyme complex essential for the replication and transcription of the viral genome [1]. It consists of three subunits: Polymerase Basic 1 (PB1), Polymerase Basic 2 (PB2), and Polymerase Acidic (PA), which function together in the nucleus of the host cell [2]. The PB1 subunit serves as the catalytic core for RNA synthesis, while PB2 binds to the 5' caps of host cellular pre-mRNAs, and PA provides the endonuclease activity necessary to cleave these caps to prime viral mRNA synthesis—a process known as cap-snatching [3]. This complex is a high-priority target for antiviral therapy because it is highly conserved across various influenza A subtypes and lacks a human homolog, reducing the likelihood of host toxicity [4]. Drugs such as baloxavir marboxil specifically inhibit the PA endonuclease, while nucleoside analogs like favipiravir target the PB1 subunit to disrupt viral RNA elongation [5]. However, the clinical utility of these drugs is often challenged by the rapid emergence of resistance-associated substitutions, such as the I38T mutation in the PA subunit [6].

Other names

RNA-dependent RNA polymerasePB1-PB2-PA complexFluA RdRpInfluenza A virus polymerase complexRNA-directed RNA polymerase catalytic subunit

The target is inhibited through several distinct mechanisms: (1) inhibition of the PA subunit's endonuclease activity, which prevents the "cap-snatching" required for viral mRNA synthesis [3, 5]; (2) inhibition of the PB2 subunit's cap-binding site to prevent host pre-mRNA recognition [2]; and (3) competitive inhibition of the PB1 subunit's polymerase activity by nucleoside analogs, leading to premature chain termination or lethal mutagenesis of the viral genome [4].