Research Applications
Antibiotic-Resistant Infections
LL-37 and its analogs are being developed as novel antimicrobials against multidrug-resistant (MDR) bacteria including MRSA, VRE, and carbapenem-resistant Enterobacteriaceae. Its membrane-disrupting mechanism is fundamentally resistant to the resistance mechanisms that defeat conventional antibiotics.
Chronic Wound Healing
LL-37 is researched for non-healing wounds (diabetic ulcers, venous stasis ulcers, pressure sores) where impaired innate immunity and biofilm formation prevent healing. Clinical trials of LL-37-based wound dressings and topical formulations are underway.
Biofilm-Related Infections
LL-37's unique anti-biofilm properties make it a candidate for treating biofilm-associated infections in prosthetic joints, catheters, and chronic wounds where conventional antibiotics fail to penetrate biofilm matrices.
Inflammatory and Autoimmune Disease
Research explores LL-37 modulation in rosacea (where LL-37 overexpression contributes to pathology), psoriasis, atherosclerosis, and inflammatory bowel disease. Understanding LL-37 regulation may yield therapeutic strategies for these conditions.
Cancer Research
LL-37 shows selective cytotoxicity against certain cancer cell types (ovarian, gastric, colon) through membrane disruption, similar to its antimicrobial mechanism. It also enhances anti-tumor immune responses through immune cell recruitment and activation.
Respiratory Infections
LL-37's role in lung innate defense makes it a candidate for treating pneumonia and respiratory infections, particularly in immunocompromised patients with reduced cathelicidin expression.
Mechanism of Action
Membrane Disruption (Antimicrobial)
LL-37 kills microorganisms through direct interaction with their cell membranes. Its cationic (+6 charge at physiological pH) and amphipathic alpha-helical structure enables electrostatic attraction to negatively charged bacterial membranes (rich in phosphatidylglycerol and lipopolysaccharide). Upon binding, LL-37 inserts into the lipid bilayer, forming toroidal pores or carpet-like disruptions that cause membrane depolarization, osmotic imbalance, and cell death.
Anti-Biofilm Activity
LL-37 is one of the most potent natural anti-biofilm agents known. At sub-antimicrobial concentrations, it prevents biofilm formation by interfering with quorum sensing, downregulating biofilm-related genes, and promoting twitching motility that prevents bacterial attachment. It can also penetrate and disrupt established biofilms.
Immunomodulation via Formyl Peptide Receptor 2
LL-37 activates the formyl peptide receptor 2 (FPR2/FPRL1) on immune cells, triggering chemotaxis of neutrophils, monocytes, and T-cells to infection sites. FPR2 activation also modulates cytokine production — enhancing anti-pathogen responses while limiting excessive inflammation.
Wound Healing Promotion
LL-37 promotes wound healing through multiple mechanisms: stimulation of epithelial cell migration and proliferation, induction of angiogenesis via VEGF upregulation, and activation of the EGFR/STAT3 signaling pathway in keratinocytes. It also recruits mesenchymal stem cells to wound sites.
LPS Neutralization
LL-37 directly binds and neutralizes lipopolysaccharide (LPS/endotoxin) from Gram-negative bacteria, preventing TLR4-mediated inflammatory signaling. This anti-endotoxin activity can protect against septic shock and excessive inflammatory responses to bacterial infection.
Biological Pathways
FPR2/ERK/NF-κB Immune Signaling
LL-37-FPR2 interaction activates ERK1/2 MAPK and NF-κB signaling in immune cells. ERK activation drives chemotaxis and degranulation, while NF-κB modulation adjusts cytokine production — enhancing TNF-α and IL-6 at infection sites while potentially suppressing excessive inflammation through context-dependent signaling.
EGFR/STAT3 Epithelial Repair
LL-37 transactivates the epidermal growth factor receptor (EGFR) in epithelial cells through metalloproteinase-mediated release of membrane-bound EGFR ligands. Downstream STAT3 activation drives epithelial proliferation, migration, and wound closure.
P2X7/NLRP3 Inflammasome
LL-37 activates the P2X7 purinergic receptor, triggering NLRP3 inflammasome assembly and IL-1β processing. This mechanism enhances intracellular pathogen clearance through pyroptosis and amplifies local immune responses.
VEGF/HIF-1α Angiogenesis
LL-37 induces VEGF expression through HIF-1α stabilization, promoting angiogenesis in wounds. New vessel formation provides oxygen and immune cell access to healing tissue, accelerating repair.
Dosage Information
Calculation Results
Syringe Fill Level (100u syringe)
Protocols
LL-37 Antimicrobial ProtocolIntermediate🛡️Immune Support10 weeks total (with 2-week washout)
Natural antimicrobial peptide for immune support, wound healing, and gut repair.
Warning: Can cause injection site irritation. Rotate sites. Start low dose.
Stability & Storage
LL-37 is supplied as a lyophilized white powder. Store at -20°C for long-term stability (12-18 months) or 2-8°C for up to 3 months. The peptide is moderately susceptible to proteolytic degradation in biological fluids.
Reconstitute with sterile water or bacteriostatic water. The solution should be clear. Store reconstituted LL-37 at 2-8°C and use within 14 days. LL-37 tends to aggregate and form oligomers in solution at higher concentrations; keep concentrations below 1 mg/mL to minimize aggregation.
The peptide is susceptible to degradation by endogenous proteases (particularly neutrophil elastase and proteinase 3) in vivo, with a half-life of approximately 30-60 minutes in serum. Various strategies to improve stability are being researched, including D-amino acid substitutions, PEGylation, and encapsulation in nanoparticles.
Side Effects & Precautions
Limited Human Safety Data
LL-37 has undergone limited clinical testing. Most safety data comes from Phase 1/2 clinical trials for wound healing applications (topical and local administration).
Local Tissue Irritation
At high concentrations, LL-37 can cause local tissue irritation due to its membrane-active properties. Cytotoxicity to mammalian cells occurs at concentrations 5-10 fold higher than antimicrobial concentrations.
Mast Cell Degranulation
LL-37 can activate mast cells through MrgX2 receptor binding, potentially causing localized histamine release, redness, and itching. This is concentration-dependent and most relevant to injection or topical administration.
Potential Pro-Inflammatory Effects
While LL-37 has anti-inflammatory properties at physiological concentrations, excessive levels can drive inflammation (as seen in rosacea). Careful dose titration is important.
Hemolytic Activity
At very high concentrations (>50 μM), LL-37 can lyse red blood cells. Therapeutic concentrations (1-10 μM) are well below this threshold.
Theoretical Autoimmune Concerns
LL-37 forms complexes with self-DNA and self-RNA that can activate plasmacytoid dendritic cells through TLR9 and TLR7, potentially triggering autoimmune responses. This mechanism is implicated in psoriasis pathogenesis but has not been observed as a side effect of exogenous administration at therapeutic doses.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Regulatory Status
LL-37 is not approved by the FDA or any major regulatory authority as a therapeutic drug. It is in clinical development, with Phase 1/2 clinical trials completed for chronic wound healing applications (venous leg ulcers).
The peptide is classified as an investigational compound and is available from peptide synthesis companies for research use. Several pharmaceutical companies and academic institutions are developing LL-37-based therapeutics and LL-37-inspired peptidomimetics for antimicrobial applications.
LL-37 is not on the WADA prohibited list and is not a controlled substance in any jurisdiction. Its primary regulatory pathway is through wound care and anti-infective drug development programs.
Research Studies
LL-37: The Only Human Member of the Cathelicidin Family of Antimicrobial Peptides
Vandamme D, Landuyt B, Luyten W, Schoofs L.
Antimicrobial Peptides: Pore Formers or Metabolic Inhibitors
Brogden KA.
LL-37 Promotes Wound Healing through EGFR Transactivation
Tokumaru S, Sayama K, Shirakata Y, et al.
Cathelicidin Anti-Biofilm Activity
Overhage J, Campisano A, Bains M, et al.
LL-37: A Multifunctional Peptide Involved in Infection and Inflammation
Kahlenberg JM, Kaplan MJ.
