LL-37 Strong Preclinical

What It Is

LL-37 is a 37-amino-acid linear peptide with the sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES, named for the two leucine residues at its N-terminus and its 37-residue length. It is the only cathelicidin antimicrobial peptide encoded by the human genome — most other mammals (cattle, pigs, sheep, horses) carry multiple cathelicidin genes; humans, mice, rats, and primates carry only one (CAMP gene on chromosome 3p21.3, four exons, ~2 kb).

LL-37 does not exist as such inside the cell. It is produced as the C-terminal cleavage product of a 170-amino-acid prepropeptide called human cationic antimicrobial peptide of 18 kilodaltons (hCAP-18). hCAP-18 contains a signal peptide, the cathelin-like prosequence (cathepsin-L-inhibitor-homologous N-terminal region that gives the family its name), and the mature C-terminal antimicrobial peptide. hCAP-18 is stored intracellularly in inactive form in the secretory granules of neutrophils, monocytes, NK cells, T and B lymphocytes, mast cells, mesenchymal stem cells, mucosal epithelial cells (skin keratinocytes, airway epithelium, GI and genitourinary tracts), and adipocytes. Upon activation, hCAP-18 is exocytosed and cleaved extracellularly: proteinase 3 in neutrophils generates active LL-37; kallikrein 5 (KLK5) in the skin generates LL-37 from keratinocyte-derived hCAP-18; other tissue-specific proteases generate context-specific cleavage variants (KS-30, KR-20, RK-31, and others) that retain partial activity with altered selectivity.

The CAMP gene is unusual among innate-immunity genes in being a direct transcriptional target of the vitamin D receptor (Gombart, Borregaard, Koeffler. FASEB J 2005;19(9):1067-77). The CAMP promoter contains a vitamin D response element (VDRE), and 1,25-dihydroxyvitamin D3 produces several-fold upregulation of CAMP mRNA in myeloid cells, keratinocytes, and other tissues. This is the mechanistic basis for why vitamin D status affects innate immunity: low serum 25-OH-D ↔ low cathelicidin tone ↔ impaired epithelial barrier defense. The vitamin D / cathelicidin axis explains a substantial portion of the seasonality and ethnic variation in respiratory and skin infection rates.

LL-37 is supplied for research use as a synthetic peptide (synthesis is straightforward — it is a linear 37-mer with no disulfide bonds or unusual modifications). Multiple research-reagent vendors (Anaspec, Bachem, Genscript, NovoPro, Peptide Sciences) supply it at ≥98% purity. There is no FDA-approved therapeutic LL-37 product; clinical-development efforts have focused on topical formulations for chronic wound healing, leg-ulcer indications, and ophthalmological use.

Mechanism of Action

LL-37 is a quintessential pleiotropic host-defense peptide — its biological output is a function of concentration, target microorganism, host cell type, and the specific cleavage variant being studied. The molecular machinery underlying this multifunctionality:

• Amphipathic α-helix in lipid environments — In aqueous solution LL-37 is largely disordered. In contact with negatively charged lipid surfaces (bacterial outer membranes, anionic phospholipid bilayers) it folds into an amphipathic α-helix with hydrophobic and cationic faces on opposite sides of the helical wheel. This conformational switch is the central biophysical event of antimicrobial activity.
• Direct membrane disruption — Folded LL-37 inserts into bacterial membranes where electrostatic attraction to anionic lipopolysaccharide (gram-negative) and lipoteichoic acid (gram-positive) outer surfaces brings the peptide into contact. The hydrophobic face partitions into the lipid bilayer, oligomerizes (recent crystal structures show tetrameric and possibly hexameric channel forms — Sci Rep 2020, s41598-020-74401-5), and forms transmembrane pores or destabilizes the bilayer through carpet-like surface coverage. Bacterial cells lyse from osmotic disruption and loss of membrane potential.
• Selectivity vs mammalian cells — Mammalian cell membranes have lower surface negative charge (cholesterol-rich, predominantly zwitterionic phosphatidylcholine outer leaflet) and resist LL-37 insertion at antimicrobial concentrations. At higher concentrations (~10–50× MIC for typical bacterial targets), LL-37 can lyse mammalian cells, providing the safety window that endogenous LL-37 exploits to attack microbes without major host-cell damage.
• LPS neutralization — LL-37 binds bacterial endotoxin (lipopolysaccharide) directly and prevents LPS engagement of TLR4/MD-2 on host immune cells. This LPS-neutralizing activity is therapeutically interesting in sepsis contexts and contributes to resolution rather than amplification of gram-negative infection inflammation.
• TLR modulation (immunomodulation) — LL-37 modulates Toll-like receptor signaling bidirectionally. It can suppress TLR2 / TLR4 / TLR9 inflammatory responses to PAMPs (Mookherjee et al., J Immunol 2006; PMID 16456005) — anti-inflammatory function. It can also potentiate TLR signaling in specific contexts: in psoriatic skin, LL-37 / self-DNA complexes activate plasmacytoid dendritic cell TLR9 to drive autoimmunity. The same peptide acts as both an inflammation suppressor and an inflammation driver depending on context, which is a defining feature of LL-37 biology and a major translational challenge.
• Chemotaxis and immune recruitment — LL-37 binds the formyl peptide receptor-like 1 (FPRL1 / FPR2) on neutrophils, monocytes, mast cells, and T cells, driving chemotactic recruitment to sites of infection. Independent receptor engagement at P2X7 and EGFR contributes to additional immune-cell signaling effects.
• Wound healing and angiogenesis — LL-37 promotes wound re-epithelialization by activating EGFR transactivation in keratinocytes, accelerating keratinocyte migration and proliferation. It also stimulates VEGF expression and endothelial cell migration, supporting angiogenesis at wound sites. Sørensen et al. and subsequent work characterized this in human keratinocyte models.
• Antiviral activity — Direct virucidal activity against enveloped viruses (HSV-1, HSV-2, influenza A, vaccinia, adenovirus partially) by disrupting viral envelope integrity. Antiviral activity at the ocular surface and respiratory epithelium is a particular focus (PMC1497871).
• Antifungal activity — Activity against Candida albicans (planktonic and biofilm forms) and other yeasts at micromolar concentrations.
• Anti-biofilm activity — LL-37 can disrupt established bacterial biofilms (Staphylococcus aureus, Pseudomonas aeruginosa) — important for chronic-wound applications.
• Synergy with conventional antibiotics — LL-37 synergizes with β-lactams (nafcillin, meropenem, piperacillin/tazobactam), peptide antibiotics, glycopeptides (vancomycin), and ceragenins. The mechanism appears to involve enhanced membrane permeability allowing greater antibiotic penetration.
• Vitamin D regulation of expression — The CAMP gene promoter contains a vitamin D response element; 1,25-(OH)₂D₃ binding to the vitamin D receptor directly upregulates CAMP transcription several-fold, increasing endogenous LL-37 production. This is the molecular basis for the vitamin-D-immunity link.

What the Research Shows

LL-37 has one of the largest preclinical literature bases of any peptide on this site — >3,000 PubMed entries spanning antimicrobial pharmacology, immunology, dermatology, oncology, and developmental biology. Major themes:

• Antimicrobial spectrum — Active against gram-positive (S. aureus including MRSA, S. epidermidis, S. pyogenes, S. pneumoniae) and gram-negative (E. coli, P. aeruginosa, K. pneumoniae, A. baumannii) bacteria with typical MICs in the 1–32 μg/mL range; activity preserved against many multidrug-resistant strains where conventional antibiotics fail. Activity against fungi (C. albicans), enveloped viruses (HSV, influenza), and biofilms documented across multiple independent labs (Wang et al. Biochim Biophys Acta 2014; PMID 24463069; Travkova et al. PMC8227053).
• Immunomodulation — Mookherjee 2006 (J Immunol; PMID 16456005) characterized LL-37's TLR-modulatory effects; LL-37 suppresses LPS-induced TNF-α release from macrophages while preserving anti-microbial chemotaxis. This bidirectional immunomodulation is the basis for LL-37's interest as both an anti-infective and an immunomodulator.
• Wound healing — Sørensen et al. and subsequent work demonstrated LL-37 expression in keratinocytes during wound healing and accelerated re-epithelialization with topical application in animal wound models. Multiple Phase 1/2 trials of synthetic LL-37 derivatives (Pep637, OP-145) for chronic venous leg ulcers and diabetic foot ulcers have been conducted.
• Inflammatory skin disease — Kim & Shimoda 2012 (PMID 22577261) — comprehensive review of LL-37 in atopic dermatitis (low cathelicidin), psoriasis (high cathelicidin / LL-37-self-DNA TLR9 activation driving autoimmunity), and rosacea (abnormal kallikrein 5 processing of hCAP-18 generating pro-inflammatory cleavage variants — PMC3904447). In rosacea, LL-37 dysregulation is now understood as a key pathogenic mechanism, leading to therapeutic interest in tetracyclines (which inhibit MMPs and may modulate cathelicidin processing) and TLR2 antagonists.
• Vitamin D / cathelicidin axis — Gombart, Borregaard, Koeffler. FASEB J 2005;19(9):1067-77. Established the CAMP gene as a direct vitamin D receptor target. This work explains the molecular basis for the well-documented seasonality of respiratory infections, the higher infection rates in vitamin D deficient populations, and the proposed protective role of vitamin D supplementation against tuberculosis and respiratory infection.
• Ocular surface — McDermott 2004 (PMC1497871) and subsequent work characterized LL-37 expression in conjunctival and corneal epithelia and demonstrated potent antibacterial and antiviral activity against ocular pathogens (P. aeruginosa, S. aureus, HSV-1, adenovirus). Topical ocular formulations have been explored.
• Cancer biology (anti-cancer evidence is mixed) — LL-37 expression is altered in multiple cancers; it can be pro-tumorigenic in some contexts (breast, ovarian, lung cancer where it promotes proliferation) and anti-tumorigenic in others (gastric cancer, colon cancer where it triggers apoptosis). PMC4485164 reviews LL-37 as both potential anticancer drug and tumor-promoting factor depending on context.
• Structure-function 3D characterization — Wang G et al. Biochim Biophys Acta 2014 (PMID 24463069); Sci Rep 2020 (s41598-020-74401-5) crystal structure of tetrameric channel-forming LL-37 in detergent micelles; multiple NMR structures of LL-37 in different lipid environments. The structural biology is unusually well characterized.
• Modified analogs — Multiple synthetic LL-37 analogs have been designed to dissociate antimicrobial activity from inflammation-driving activity: D-LL-37 (D-amino acid version, more stable), KS-30, OP-145, and others. These represent the active drug-discovery pipeline for cathelicidin therapeutics.

Human Data

Human LL-37 data falls into two categories: endogenous LL-37 expression studies (correlative / observational) and small Phase 1/2 trials of exogenous LL-37 or its analogs:

• Topical synthetic LL-37 for chronic venous leg ulcers — Multiple small Phase 1/2 trials in Europe (Pep637, Promore Pharma; later Lipopeptide AB) studied topical synthetic LL-37 application to hard-to-heal venous leg ulcers. Acceptable safety; modest efficacy signals on wound-area reduction and re-epithelialization speed; no large Phase 3 confirmation.
• OP-145 ear drops for chronic suppurative otitis media — OP-145 is a synthetic LL-37-derived peptide developed for chronic ear infections. Phase 2 trials demonstrated antibacterial efficacy and acceptable safety in ear-drop formulation.
• Endogenous LL-37 levels and disease association — Large body of observational human research linking LL-37 levels to disease states: low LL-37 in atopic dermatitis (correlates with skin infection susceptibility), high LL-37 in psoriasis and rosacea (correlates with inflammation severity), low LL-37 in active tuberculosis and respiratory infection (correlates with vitamin D deficiency), reduced LL-37 in inflammatory bowel disease, altered LL-37 in periodontal disease, and many more correlations.
• Vitamin D supplementation studies — Multiple human studies have shown that oral vitamin D supplementation in deficient adults produces measurable upregulation of cathelicidin (LL-37) production from monocytes and keratinocytes — confirming the vitamin D / CAMP transcriptional axis works in vivo. Hata et al. and others demonstrated this in atopic dermatitis subjects.
• Anti-LL-37 autoantibodies in psoriasis — Small clinical studies have identified LL-37 / self-DNA complexes and anti-LL-37 antibodies in psoriasis patient sera, supporting the autoimmunity-driving role of LL-37 in that disease.
• No native-LL-37 systemic therapeutic trials — No published Phase 2/3 trial of systemic (parenteral) native LL-37 for any indication. Systemic administration faces challenges including rapid proteolytic degradation, broad pleiotropy, and dose-dependent host-cell toxicity at higher concentrations.
• Anecdotal community use — A small number of self-experimenters use synthetic LL-37 SubQ for "immune support" or "gut healing" applications. These reports lack controlled evidence and are unsupported by safety data; SubQ delivery of native LL-37 has not been characterized in any published clinical trial.

Dosing from the Literature

LL-37 dosing varies dramatically across context — endogenous physiological concentrations, in-vitro antimicrobial assays, topical wound-healing trials, and community SubQ self-administration each operate at very different scales.

Reconstitution & Storage

Synthetic LL-37 is supplied for research use as a lyophilized peptide:

• Solubility — LL-37 is amphipathic and surface-active; reconstitute in low-ionic-strength buffer or dilute acetic acid for stable stocks. Avoid high-ionic-strength buffers for storage (LL-37 antimicrobial activity is salt-sensitive at physiological NaCl concentrations).
• Adsorption — LL-37 binds to plastic and glass surfaces; use low-binding tubes for stock preparation, and avoid prolonged exposure to large surface areas.
• Storage — Lyophilized peptide stable for years at −20°C in dark, desiccated conditions. Reconstituted aliquots stable for months at −80°C with avoidance of repeated freeze-thaw.
• Sterility / endotoxin — Synthetic LL-37 for in-vivo or any human-relevant research application requires endotoxin testing; LPS contamination interferes with LL-37 immunological assays and confounds in-vivo administration.

→ Use the Kalios Dosing Calculator for vial conversions

Side Effects & Risks

Native LL-37 has no approved therapeutic application, so the risk profile is drawn from in-vitro and small clinical-trial data plus mechanistic considerations:

• Host-cell membrane disruption at high concentrations — Above ~10–50× MIC for typical bacterial targets (~50–500 μg/mL local), LL-37 begins to lyse mammalian cells. This is the safety-window ceiling for any LL-37 therapeutic.
• Inflammation amplification (autoimmunity risk) — In psoriatic skin, LL-37 forms complexes with self-DNA and self-RNA released from injured cells, activating plasmacytoid dendritic cell TLR9/TLR7. This drives type I interferon production and downstream T-cell mediated autoimmunity. Patients with active psoriasis or psoriatic-spectrum autoimmunity should not use exogenous LL-37.
• Rosacea aggravation — Abnormal kallikrein-5 processing of LL-37 in rosacea generates pro-inflammatory cleavage variants. Exogenous LL-37 in rosacea-prone skin could plausibly exacerbate flare severity. Documented contraindication for any topical formulation.
• Allergic / hypersensitivity — As an endogenous human peptide, native LL-37 is non-immunogenic in most contexts, but synthetic batches with N-terminal modifications or impurities can produce hypersensitivity. Animal-derived cathelicidin from bovine/porcine sources used in some research contexts is more immunogenic and not appropriate for human-relevant work.
• Bacterial resistance development — A theoretical concern raised against any antimicrobial-peptide therapeutic. Some bacteria (Staphylococcus aureus aps gene system, Pseudomonas aeruginosa LPS modifications) have evolved cathelicidin-resistance mechanisms; large-scale therapeutic LL-37 use could plausibly select for these resistance phenotypes.
• Cancer biology (mixed direction) — LL-37 has both pro- and anti-tumorigenic effects depending on cancer type. Patients with active or recent cancer should use synthetic LL-37 only under specialist supervision, given the unpredictable directional effect.
• Pregnancy and lactation — Endogenous LL-37 is normal in pregnancy; exogenous synthetic LL-37 has not been characterized in pregnancy. Avoid where possible.
• Sourcing / purity / endotoxin — As a synthetic 37-mer, LL-37 quality varies between vendors. Independent third-party Certificate of Analysis (HPLC purity ≥98%, mass-spec confirmation, endotoxin testing for in-vivo applications) is the practical floor for due diligence.
• Drug interactions — Synergy with β-lactams and many conventional antibiotics is well-documented; this can be therapeutic but also could amplify antibiotic toxicity in unintended ways. Concurrent statin therapy may upregulate endogenous LL-37 (statins enhance vitamin D / cathelicidin axis), potentially augmenting effects.

Bloodwork & Monitoring

No clinical monitoring guidelines exist for LL-37 administration; monitoring is principally for endogenous LL-37 status and the vitamin D pathway that regulates it:

• Vitamin D (25-OH) — Target 40–60 ng/mL for optimal endogenous CAMP / LL-37 expression. Baseline and seasonal recheck. The single most actionable lab affecting endogenous LL-37 tone.
• CBC with differential — Neutrophils are the principal LL-37-storing cell; neutropenia limits LL-37 reserves. Document baseline.
• Plasma cathelicidin / LL-37 assays — Available through specialty research labs (ELISA-based, Hycult Biotech and similar). Reference range ~1–5 μg/mL. Useful for research and rare clinical contexts (e.g., chronic recurrent infections).
• Inflammatory markers — hs-CRP, ESR baseline; can rise with cathelicidin pathway activation.
• Skin examination — Document baseline psoriasis, rosacea, atopic dermatitis history before any topical or community-administered LL-37 exposure given the disease-amplification risk.
• Skin / gut microbiome — Theoretical: LL-37 alters microbial community composition. Not standard clinical monitoring.

Commonly Stacked With

LL-37 has no established clinical stacking literature outside antimicrobial synergy data. Conceptually relevant pairings:

→ Check compound compatibility in the Stack Builder

Regulatory Status

Related Compounds

Innate-immunity and tissue-repair peptides that sit next to LL-37 in the host-defense toolkit.

Next Steps

Key References

1. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005;19(9):1067-1077. PMID: 15985530. (The defining vitamin D / cathelicidin transcription paper.)
2. Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, Roche FM, Mu R, Doho GH, Pistolic J, Powers JP, Bryan J, Brinkman FS, Hancock RE. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J Immunol. 2006;176(4):2455-2464. PMID: 16456005. (Foundational TLR-modulation paper.)
3. Mookherjee N, Hancock RE. Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci. 2007;64(7-8):922-933. PMID: 17310276.
4. Wang G, Mishra B, Epand RF, Epand RM. High-quality 3D structures shine light on antibacterial, anti-biofilm and antiviral activities of human cathelicidin LL-37 and its fragments. Biochim Biophys Acta. 2014;1838(9):2160-2172. PMID: 24463069. (Structural biology review.)
5. Sancho-Vaello E, Gil-Carton D, François P, Bonetti EJ, Kreir M, Pothula KR, Kleinekathöfer U, Zeth K. The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics. Sci Rep. 2020;10(1):17356. (Crystal structure of tetrameric channel-forming LL-37.) DOI: 10.1038/s41598-020-74401-5.
6. Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol. 2012;24(2):126-135. PMID: 22577261.
7. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner RA, Bonnart C, Descargues P, Hovnanian A, Morhenn VB, Gallo RL. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-980. PMID: 17676051. (Rosacea pathogenesis paper.)
8. McDermott AM. Antimicrobial compounds in tears. Exp Eye Res. 2013;117:53-61. (Ocular surface AMP review.)
9. Gordon YJ, Huang LC, Romanowski EG, Yates KA, Proske RJ, McDermott AM. Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr Eye Res. 2005;30(5):385-394. PMID: 16020268. (PMC1497871.)
10. Schauber J, Gallo RL. The vitamin D pathway: a new target for control of the skin's immune response? Exp Dermatol. 2008;17(8):633-639. PMID: 18573153. (Vitamin D / cathelicidin in skin immunity review.)
11. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415(6870):389-395. PMID: 11807545. (Foundational AMP review.)
12. Travkova OG, Moehwald H, Brezesinski G. The interaction of antimicrobial peptides with membranes. Adv Colloid Interface Sci. 2017;247:521-532. (Membrane disruption mechanism.)
13. Aoki W, Ueda M. Characterization of antimicrobial peptides toward the development of novel antibiotics. Pharmaceuticals (Basel). 2013;6(8):1055-1081. (Therapeutic AMP development context.)
14. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 Suppl 1):S15-S26. PMID: 24229632. (Rosacea LL-37 mechanism review.)
15. Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009;30(3):131-141. PMID: 19217824.
16. Kahlenberg JM, Kaplan MJ. Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol. 2013;191(10):4895-4901. PMID: 24185823. (Autoimmunity-driving role.)
17. Antimicrobial Peptides of the Cathelicidin Family: Focus on LL-37 and Its Modifications. Int J Mol Sci. 2025;26(16):8103. (Recent comprehensive review.)
18. The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent. Antibiotics (Basel). 2021. PMC: PMC8227053. (Antibiofilm and synergy review.)
19. Innate immunity and the role of the antimicrobial peptide cathelicidin in inflammatory skin disease. PMC: PMC3904447. (Inflammatory skin disease review.)
20. Human antimicrobial/host defense peptide LL-37 may prevent the spread of a local infection through multiple mechanisms: an update. Inflamm Res. 2025. DOI: 10.1007/s00011-025-02005-8. (Most recent comprehensive update.)