Discovery of Encrypted Peptides in a Human Matrix Metallopeptidase

: The human proteome represents a vast, largely untapped source of encrypted bioactive peptides with therapeutic potential. Here, we report the discovery and functional characterization of three antimicrobial encrypted peptides (EPs) derived from human matrix metallopeptidase-19 (residues 1-19, 1-33, and 247-279). These peptides exhibit potent, broad-spectrum activity against Gram-positive and Gram-negative bacteria, including clinical isolates and multidrug-resistant strains. Mechanistic studies reveal membrane depolarization and permeabilization as the primary mechanism of action. The peptides also inhibit biofilm formation, eradicate preformed biofilms, and exhibit selective antiviral activity against enveloped viruses. Importantly, they display negligible hemolysis and cytotoxicity toward mammalian cells while modulating inflammation through LPS neutralization. Synergy assays reveal synergistic or additive interactions with last-line antibiotics, and no resistance emerged after serial bacterial passaging. A fully d-amino acid analog of the lead peptide retained activity and exhibited cytocompatibility and in vivo efficacy in a murine skin infection model. These findings underscore the therapeutic promise of human protein-derived encrypted peptides and highlight proteome mining as a viable strategy for identifying host-compatible anti-infectives.