Discovery of Novel Antiviral Scaffolds, Potent Inhibitors of Respiratory Syncytial Virus Fusion

Abstract

Respiratory syncytial virus (RSV) is a major cause of respiratory infections, particularly in infants, older adults, andother vulnerable populations. Although three vaccines have recently been approved to prevent RSV infection inpregnant women and adults aged 60 years and above, there remains a significant unmet need for effective antiviraltherapeutics for the treatment of established RSV infections. Previously reported RSV inhibitors have been limitedby insufficient clinical evidence, emergence of antiviral resistance, safety concerns, high cost, and challengesassociated with the competitive antiviral market.Our preliminary results have identified a promising series of novel RSV fusion inhibitors exhibiting exceptionalantiviral potency, with IC 50 values ranging from <0.01 to 4.89 nM against a panel of RSV A and B laboratorystrains. Several compounds demonstrate potency approaching 100-fold greater than that of previously reportedleading compounds, highlighting their potential as next-generation RSV therapeutics.The proposed project will focus on the systematic discovery and optimization of highly potent and selective RSVfusion inhibitors targeting the prefusion form of the RSV F protein. Screening and medicinal chemistry approacheswill be employed to identify antibody-mimetic compounds capable of recognizing key F-protein epitopes, as wellas novel heterocyclic scaffolds, including thiazole, thiophene, and quinoxaline-based derivatives, designed tointeract selectively with the fusion peptide or heptad-repeat regions. Comprehensive structure activity relationship(SAR) studies will guide optimization of potency, binding affinity, physicochemical properties, pKa, aqueoussolubility, oral bioavailability, pharmacokinetics, and selectivity while minimizing toxicity and off-target effects.The project is expected to deliver optimized lead candidates with favorable pharmacokinetic and pharmacodynamicprofiles, improved bioavailability, prolonged half-life, reduced toxicity, and enhanced selectivity toward the RSV Fprotein. The anticipated outcomes include 1-2 patent applications and 3-4 high-quality research publications inmedicinal chemistry and organic synthesis journals. Ultimately, this integrated drug-discovery strategy is expectedto provide promising therapeutic candidates and establish new chemical frameworks for the effective treatment ofRSV infections.