Alpha-Defensins (HNP-1 to HNP-4)

Endogenous

Alpha-defensins are a family of small (29-35 amino acid), cysteine-rich cationic peptides that constitute a major component of the innate immune system. Human neutrophil peptides (HNP-1 through HNP-4) are stored in azurophilic granules of neutrophils, where they comprise 5-7% of total neutrophil protein. Upon neutrophil degranulation at sites of infection, alpha-defensins are released at locally high concentrations, directly killing or inhibiting bacteria, fungi, and enveloped viruses through membrane disruption. Their mechanism exploits a fundamental difference between microbial and mammalian cell membranes — microbial membranes have negatively charged phospholipids in their outer leaflet, which attracts the cationic defensin peptides, while mammalian cell membranes have neutral outer leaflets. Beyond direct antimicrobial activity, alpha-defensins serve as immunomodulatory signaling molecules. They recruit and activate dendritic cells, promote T-cell responses, stimulate mast cell degranulation, and enhance phagocytosis. Two additional alpha-defensins — HD-5 and HD-6 — are expressed by Paneth cells in the small intestinal crypts, where they regulate the composition of the gut microbiome and protect against enteric pathogens. Dysregulation of defensin expression is implicated in inflammatory bowel disease, periodontitis, and susceptibility to sexually transmitted infections. Research interest in synthetic defensin analogs focuses on developing novel antimicrobial agents to combat antibiotic-resistant bacteria, as defensin-mediated killing is mechanistically distinct from conventional antibiotics and resistance development is theoretically more difficult.