Targeting emerging respiratory pathogens with clamp peptides: Broad-spectrum inhibition of viral entry in 3D human lung models.

Rapid urbanization, migration, and climate change are accelerating the appearance and diversification of respiratory viruses, overwhelming the pace at which conventional drugs can be discovered and manufactured. Here, we report a fast-response platform based on 15- to 25-residue "clamp peptides" (CPs) that grip conserved receptor-binding domains of viral surface proteins. Developed through rational structure-based docking and supported by retrospective machine learning triage, CPs bind their targets and potently block viral entry across SARS-CoV-2 variants and influenza A strains in human tissue-engineered 3D lung models by 2-4 log10, without cytotoxicity or hemolysis at therapeutically relevant concentrations. Unlike antibodies, proteins, or small molecules, CPs are synthetic, reproducible, and rapidly designable to specific domains. This work establishes CPs as a scalable, broad-spectrum, and variant-agnostic platform amenable for use in intranasal delivery to block viral entry of respiratory viruses at the airway mucosa, offering a valuable first-line countermeasure for future respiratory outbreaks.