# Discovery of Encrypted Peptides in a Human Matrix Metallopeptidase

## TL;DR

Researchers discovered three antimicrobial peptides from a human enzyme that show strong activity against bacteria and viruses, with low toxicity and potential for drug development.

## Contribution

Identification of encrypted peptides from human matrix metallopeptidase-19 with broad therapeutic potential.

## Key findings

- The peptides show potent activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains.
- They inhibit biofilm formation and exhibit selective antiviral activity against enveloped viruses.
- A d-amino acid analog of the lead peptide retained activity and showed in vivo efficacy in a skin infection model.

## Abstract

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.