LL-37

What it is

LL-37 is a 37-amino-acid antimicrobial peptide derived from the C-terminal end of human cathelicidin antimicrobial protein-18 (hCAP-18). The “LL” in the name refers to the two leucine residues at the N-terminus of the active fragment. LL-37 is the only cathelicidin in humans (other species have multiple cathelicidins) and is part of the human innate immune system.

LL-37 is produced by neutrophils, mast cells, NK cells, B-cells, and epithelial cells throughout the body — particularly at barrier surfaces (skin, gut, respiratory tract, urinary tract). Vitamin D is a known transcriptional regulator of LL-37 production.

Synthetic LL-37 has been used in laboratory research for decades. It is not FDA-approved for any indication. The peptide and its analogs are an active area of antimicrobial drug development research.

Mechanism of action

Proposed mechanisms come from laboratory and animal research:

• Membrane disruption: in laboratory studies, the peptide’s amphipathic α-helical structure has been reported to insert into bacterial membranes and disrupt membrane integrity. Laboratory activity has been reported against gram-positive and gram-negative bacteria, fungi, and enveloped viruses.
• Biofilm activity: in laboratory studies, LL-37 has been reported to show activity against some biofilm-forming organisms.
• Resistant organisms: in laboratory (cell culture) studies, activity has been reported against MRSA, VRE, and certain multidrug-resistant gram-negative bacteria.
• Immunomodulation: in laboratory and animal studies, LL-37 has been reported to influence inflammatory signaling and immune cell function; the effects varied with concentration and context.
• Endotoxin binding: in laboratory studies, LL-37 has been reported to bind lipopolysaccharide (LPS) from gram-negative bacteria.
• Tissue repair signaling: in cell and animal studies, LL-37 has been associated with changes in re-epithelialization.

Research findings

Most of the LL-37 literature is preclinical (laboratory and animal). In observational research, low endogenous LL-37 levels have been associated with susceptibility to certain chronic infections and inflammatory skin conditions.

Chronic infection and biofilm states: laboratory and animal studies have explored LL-37 in chronic wound infection and biofilm models and reported antimicrobial activity in those settings.

Inflammatory skin conditions: research has linked endogenous LL-37 to psoriasis (where overproduction may contribute) and atopic dermatitis (where deficiency may contribute).

Severe infection: small preclinical studies have explored LL-37 in models of severe infection.

Wound healing: a small early-phase study of topical LL-37 in chronic leg ulcers has been published; benefit in people has not been established.

Well-controlled human trials establishing effectiveness and safety are lacking.

Side effects and contraindications

Human safety of synthetic LL-37 has not been established in well-controlled trials, and long-term effects are unknown. Because of its reported immune-modulating activity, concerns have been raised for people with autoimmune conditions (including psoriasis) or those taking immunosuppressive medications. No safety data are available for pregnancy or breastfeeding. Products sold outside regulated channels (e.g., “research peptides”) may vary in purity, dose, and sterility.

What we don’t yet know

How synthetic LL-37 compares with conventional antibiotic approaches for specific infections has not been studied in head-to-head trials. The role of LL-37 in modulating the broader microbiome (vs. acting only on pathogenic organisms) is an area of active research. Long-term human safety is not characterized. Formal trial data that would define whether LL-37 is effective or safe for any indication are not currently available.