LL-37

LL-37 is the only cathelicidin antimicrobial peptide found in humans. The name derives from its first two amino acids (both Leucine, abbreviated 'L') and its total length of 37 amino acids. It is cleaved from the C-terminus of the 18 kDa precursor protein hCAP-18 (human cationic antimicrobial protein) by proteinase 3 in neutrophils and by kallikreins in skin. Stored in neutrophil specific granules and secreted by epithelial cells, LL-37 is a first-line innate immune defense peptide expressed by the CAMP gene on chromosome 3.

LL-37 (under the pharmaceutical name Ropocamptide, developed by Promore Pharma in Sweden) completed a Phase I/IIa clinical trial with 34 patients with hard-to-heal venous leg ulcers. The 0.5 mg/mL topical formulation demonstrated a 6-fold greater healing rate compared to placebo over 4 weeks. A larger 148-patient Phase IIb trial has also been completed. The wound healing mechanism involves LL-37's combined antimicrobial, anti-biofilm, angiogenic, and keratinocyte migration-promoting activities.

Unlike conventional antibiotics that target specific molecular pathways (which bacteria can evolve resistance to), LL-37 kills bacteria through physical membrane disruption — its cationic charge attracts it to anionic bacterial membranes, and its alpha-helical structure creates pores that rapidly lyse the cell. This physical mechanism makes resistance development much more difficult. Additionally, LL-37 disrupts bacterial biofilms, which are the primary reason chronic wound infections resist antibiotic treatment, and it recruits immune cells to clear remaining bacteria.

Vitamin D directly induces the expression of the CAMP gene that encodes hCAP-18 (the LL-37 precursor protein). The vitamin D receptor (VDR) binds to a vitamin D response element in the CAMP promoter, upregulating LL-37 production. This molecular mechanism is a key reason vitamin D supplementation supports immune function — it boosts the body's production of its primary antimicrobial peptide. Vitamin D deficiency is associated with reduced LL-37 levels and increased infection susceptibility.

LL-37 demonstrates concentration-dependent hemolytic activity — at higher systemic concentrations needed for parenteral antimicrobial therapy, the peptide's membrane-disrupting mechanism also affects human red blood cells. Additionally, serum proteins partially bind and inactivate the peptide, and its half-life in circulation is short due to rapid proteolytic degradation. This is why clinical development has focused on topical wound application, where high local concentrations can be achieved without systemic hemolysis concerns.

LL-37 provides a fundamentally different approach: rather than targeting a single bacterial pathway, it physically disrupts membranes, neutralizes endotoxin, destroys biofilms, recruits immune cells, and simultaneously promotes wound healing through angiogenesis and keratinocyte migration. Conventional antibiotics kill bacteria but do not promote healing, cannot penetrate biofilms effectively, and face resistance evolution. LL-37 addresses all these limitations while remaining effective against antibiotic-resistant strains including MRSA and multi-drug resistant Pseudomonas.