Structure-guided identification of a PrPC-binding peptide derived from Brucella abortus Hsp60 for receptor-mediated mucosal targeting.

Here, we report the structure-guided identification pipeline of a novel PrPC-binding peptide, PEP1, derived from Brucella abortus Hsp60 through computational docking. Computational modeling predicted that PEP1 engages the PrPC binding interface with favorable binding energetics, motivating its experimental evaluation as a receptor-targeting ligand. Fusion of PEP1 to a model protein enabled receptor-mediated targeting to intestinal M-cell-associated regions and resulted in increased mucosal IgA and systemic IgG responses relative to the untargeted protein. Together, these findings establish PEP1 as a minimal peptide ligand that promotes receptor-mediated antigen uptake through M cells, demonstrating the utility of structure-guided approaches for discovering functional targeting peptides.