A scoping review of influenza RdRp-targeting inhibitors: mechanisms, clinical translation, and emerging challenges.

Background: Although the RNA-dependent RNA polymerase (RdRp) complex is a therapeutic target for influenza, evidence on the pharmacology, resistance, and clinical impact of RdRp-targeting inhibitors in high-risk populations remains fragmented. This scoping review on RdRp-targeting inhibitors identifies the research gaps and characterizes their mechanisms of action, pharmacokinetics, efficacy, safety, and resistance patterns. Methods: Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews" guidelines, a comprehensive search for studies was conducted across PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang, and ClinicalTrials.gov from inception to October 2025. Preclinical and clinical studies on influenza RdRp-targeting inhibitors were included, with data charted across eight domains. Results: From 1,282 identified records (English: 1197; Chinese: 85), 156 articles were included. PA inhibitors emerged as the most extensively documented class. Preclinical findings demonstrated potent antiviral activity of PA inhibitors and emerging PB1/PB2 analogs, with variability in pharmacokinetic profiles. Clinical evidence showed PA inhibitors consistently shorten the time to symptom relief and accelerate viral RNA clearance compared with standard therapy. RdRp-targeting inhibitors showed an acceptable tolerability profile. Resistance was a notable challenge, primarily involving PA-I38 substitutions. Evidence on drug-drug interactions was limited to early-phase trials. A significant evidence gap remains for high-risk populations; baloxavir being the only agent widely studied in high-risk adults. Conclusion: RdRp-targeting antivirals represent a promising frontier for influenza treatment, with PA inhibitors being the most extensively validated class. While PB1 and PB2 inhibitors diversify the therapeutic pipeline, their development is hindered by the need for multiple-dose regimens and the emergence of drug resistance. Future research should prioritize inhibitor designs that minimize resistance, as well as combination regimens, to accelerate clinical translation.