AI-Guided Multitargeting Inhibitor Provides Potent RSV Therapy by Blocking Viral Entry and Replication Dynamics
Respiratory syncytial virus (RSV) causes severe respiratory disease, and therapies are limited by resistance. To overcome limitations of single-target RSV drug discovery, we used an artificial intelligence (AI)-driven platform to screen 696,222 natural products and identified isochlorogenic acid B (ICAB) as a multitarget inhibitor. ICAB demonstrated nanomolar activity against RSV A/B subtypes and clinical isolates (IC50: 13-435 nM) and remained effective against strains resistant to approved and late-stage anti-RSV agents. Mechanistically, ICAB inhibited viral attachment, membrane fusion, and replication by targeting G, F, and M2-1, respectively. Serial passaging showed a high genetic barrier: a >10-fold IC50 increase required 20 passages versus 10-15 for comparator drugs, with escape mediated primarily by mutations in G, F, and M2-1. In mice, ICAB reduced pulmonary viral loads and inflammation after oral or intranasal dosing, even with delayed treatment. These findings support ICAB as a promising resistance-resilient anti-RSV candidate.