Respiratory Syncytial Virus (RSV) Small-Molecule Therapeutics Sail Between Scylla and Charybdis Toward Clinical Breakthroughs

• This review ruminates on two decades of RSV small-molecule discovery efforts, revealing that limited antiviral potency, inadequate oral exposure, delayed dosing, and rapid resistance mutations drive most clinical failures. • Structure-guided crystallography and artificial intelligence reshape legacy inhibitor scaffolds, diversify chemotypes, enhance binding to flexible fusion pockets, and widen coverage against existing and emerging resistance variants. • Emerging preclinical models could replicate neonatal and geriatric infection kinetics, enabling regimen optimization, reliable pharmacokinetic correlations, and predictive progression to randomized clinical studies. The recurrent morbidity of respiratory syncytial virus (RSV) in infants and older adults underscores the need for accelerated antiviral discovery. However, no small-molecule therapeutics have received approval. This review systematically evaluates two decades of structure-activity relationships, druggability assessments, and clinical outcomes. These involve key representative and clinically evaluated inhibitors of the RSV fusion protein, large polymerase, and nucleoprotein. Analyses of past trials identify multiple principal causes of attrition. These include limited antiviral potency, inadequate oral exposure, delayed treatment initiation, and the rapid emergence of resistance. Furthermore, clinical translation faces stringent pharmacokinetic and safety constraints specific to pediatric populations. The development of small-molecule drugs has thus been slowed by repeated clinical failures and persistent scientific challenges. Nevertheless, knowledge accumulated from previous efforts provides a solid foundation. Concurrently, emerging technologies offer new opportunities. Recent crystallographic insights into target flexibility and escape mutations now guide the redesign of legacy scaffolds. Additionally, targeting host factors presents a promising strategy to counter viral immune evasion and resistance. Virtual screening driven by artificial intelligence and lead discovery based on structures efficiently expand chemical diversity. Chimeric mouse models and microphysiological systems, such as human airway organoids and organ-on-a-chip devices, enhance predictions of pharmacokinetics and pharmacodynamics. Accordingly, this review proposes a multidisciplinary roadmap that integrates chemistry guided by structures, predictive preclinical models, and optimized clinical protocols. Implementing these strategies could accelerate development timelines and deliver effective RSV small-molecule therapeutics to vulnerable populations. Table of Contents