Targeting Influenza Virus RdRp PB2 Subunit: Advances in Inhibitor Development for Antiviral Therapy

Influenza remains a significant global health challenge, causing seasonal outbreaks and occasional pandemics. Current antiviral treatments are often limited by the virus’s rapid mutation and the emergence of drug resistance. The RNA-dependent RNA polymerase (RdRp) complex, composed of PA, PB1, and PB2 subunits, is crucial for viral replication, with PB2 playing a key role in binding host pre-mRNA during viral RNA synthesis. Targeting PB2 has become an attractive strategy for developing novel antivirals. In recent years, several small-molecule inhibitors have been identified that specifically disrupt PB2’s function, offering a promising approach to halting viral replication. This review explores the discovery and development of PB2 inhibitors, focusing on their structure-activity relationships and mechanisms of action. It also evaluates their effectiveness against various influenza strains, including drug-resistant variants, and highlights challenges in advancing PB2-targeted therapies. By analyzing current progress, this review aims to provide insights for future research in developing more effective antiviral strategies against influenza.