Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics

The rapid evolution of influenza viruses, driven by high mutation rates and cross-species transmission, underscores the importance of discovering antivirals with novel mechanisms of action and distinct resistance profiles. The influenza virus RNA polymerase, a highly conserved heterotrimeric complex, comprises polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) in influenza A and B viruses, or polymerase 3 protein (P3) in influenza C and D viruses. This complex is essential for viral genome replication and transcription, rendering it a critical target for antiviral intervention. Over the past two decades, research on influenza polymerase (FluPol) has advanced from fundamental studies to drug development and clinical application. By 2025, six FluPol-targeting drugs have received regulatory approval: the PA inhibitors baloxavir marboxil, suraxavir marboxil, seloxavir marboxil, and pixavir marboxil; the PB1 inhibitor favipiravir; and the PB2 inhibitor onradivir, with several additional candidates progressing to clinical research. This review summarizes the structure and function of influenza polymerase and the mechanisms of action of different inhibitors, highlighting the discovery and clinical effectiveness of the newly approved FluPol-targeting drugs. It addresses the potential of FluPol inhibitors against highly pathogenic avian influenza and the challenges posed by resistance mutations.