LL-37

LL-37 is a 37-residue linear, α-helical peptide with the sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES and a net charge of +6. It is the only cathelicidin-derived antimicrobial peptide in humans, produced by proteolytic cleavage from the 18-kDa precursor hCAP18, itself encoded by the single human cathelicidin gene CAMP as a pro-peptide comprising an N-terminal cathelin domain and a C-terminal antimicrobial region.

Its name comes from its two leading leucine residues in the 37-residue mature form isolated from human granulocytes. Unlike the disulfide-bonded β-sheet defensins, it has no disulfide bonds. On the skin surface, active cathelicidin peptides are released from the inactive precursor by kallikrein-family serine proteases, specifically kallikrein 5 and kallikrein 7.

Mechanism

As an antimicrobial peptide, LL-37 is amphipathic and cationic, with broad reported activity against gram-positive and gram-negative bacteria, viruses and fungi, and antifungal activity described in Candida infection. Reviews describe its interaction with lipid bilayer surfaces and membrane disruption; they also state that the mechanisms by which it prevents bacterial biofilm formation have not been well understood.

The wound-healing rationale is separate and more circumstantial. Endogenous LL-37 was found abundantly in acute wounds but absent from chronic wounds, and it was described as involved in re-epithelialisation of human skin wounds and as lacking in chronic ulcer epithelium; local administration stimulated healing of chronic wounds in experimental animals and in an ex vivo model of human acute wounds, and antibodies against LL-37 inhibited healing. The trial literature states that the mechanism by which LL-37 increases healing is not fully understood but likely involves re-epithelialisation, angiogenesis and inflammation.

Evidence status

LL-37 is not an approved medicine. A 2024 review states no regulatory approval for LL-37, its derivatives or any LL-37-based compound, and notes that very few peptide-based compounds have become pharmaceutical products. In wound care specifically, the trial literature states there are no approved prescription products for oral or topical treatment of hard-to-heal venous leg ulcers; synthetic LL-37 is an investigational medicinal product under development as ropocamptide.

Two human trials are on record. An earlier Phase I/II trial in 34 venous leg ulcer patients in Sweden, with a placebo run-in followed by randomised double-blind treatment, reported that supplementing non-healing ulcers with synthetic LL-37 significantly enhanced the healing rate without systemic safety or local tolerability concerns — but with a non-monotonic pattern in which the highest-exposure arm showed no improvement. The subsequent HEAL LL-37 trial, a Phase IIb double-blind randomised placebo-controlled study across 15 sites in Poland and Sweden with 149 participants randomised, did not identify any significant improvement in healing in the full study population; a post hoc analysis of patients with large target wounds found significant improvement in several interrelated healing parameters, and the drug was well tolerated in both strengths tested.

What the literature does not establish

• The Phase IIb trial's primary efficacy analysis in the full population was negative, so efficacy for hard-to-heal venous leg ulcers is not established.
• The large-wound benefit comes from a post hoc subgroup analysis that the authors state was not designed or powered for that comparison; they call for an adequately powered study.
• The mechanism by which LL-37 increases healing is stated not to be fully understood, and the reason for the different response in large versus small ulcers is described as elusive.
• No regulatory authority has approved LL-37 or an LL-37-derived compound for any indication.
• Reviews note emerging bacterial resistance to LL-37 and unresolved, sometimes opposite, roles in cancer and in inflammatory skin disease, with conflicting expression findings in atopic dermatitis.

Sources

• LL-37: structures, antimicrobial activity and influence on amyloid-related diseases (PMC) — establishes the 37-residue sequence, net charge, helical structure, hCAP18 precursor relationship, the absence of any approved LL-37 compound, and the stated mechanistic gaps.
• Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers (PMC) — the Phase I/II and Phase IIb HEAL trial designs and outcomes, the negative full-population result, the post hoc large-wound subgroup finding, and the investigational status as ropocamptide.
• Cathelicidin LL-37: An Antimicrobial Peptide with a Role in Inflammatory Skin Disease (PMC) — the CAMP gene and kallikrein 5 and 7 processing, the antimicrobial spectrum, and the conflicting findings in atopic dermatitis and psoriasis.