Potent Antivirals for Respiratory Syncytial Virus Detected via Peptide-Based Fusion Inhibitor Screening

Abstract The respiratory syncytial virus (RSV) causes fatal pneumonia in neonates, infants, and older adults. However, no approved antiviral drugs exist for RSV; furthermore, the currently available antibody-based therapies are expensive and do not provide complete protection against RSV infections. Thus, developing anti-RSV agents for treating RSV infections is crucial. We previously established a rational strategy for designing peptide-based fusion inhibitors targeting class I fusion proteins, which are essential for the membrane fusion of viruses and host cells. Here, we used this strategy to identify peptide-based fusion inhibitors that block the interaction between the heptad repeat 1 and 2 (HR1 and -2) regions of the RSV F protein and identified four key amino acid regions involved in the HR1–HR2 interaction. Peptides, including the key amino acid regions VirRS2 and VirRS8, inhibited the replication of the RSV-A2 strain. We confirmed the structure–activity relationships using crystal structure coordinates and AlphaFold2-based structural predictions. These results may advance novel RSV fusion inhibitor development.