LL-37: The Human Cathelicidin Peptide in the Research Literature

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

This article explains what LL-37 is, how it was predicted from a bone-marrow cDNA library in 1995 and then isolated from granulocytes, what NMR and crystallography have shown about how it sits on membranes, what the immunology cell studies measured, why it is a standard reagent in microbiology laboratories, and what a certificate should show for a highly cationic 37-residue peptide with no aromatic chromophore.

LL-37 is the 37-residue C-terminal peptide of the only human cathelicidin

LL-37 is Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu-Ser, named for its two N-terminal leucines and its length. It is cut from the C-terminus of hCAP18, an 18 kDa precursor encoded by the CAMP gene, which is the single cathelicidin gene in humans. With eleven basic residues (six lysines, five arginines) against five acidic ones, the peptide carries a net charge near +6 at neutral pH. It contains no cysteine, no tryptophan and no tyrosine, which has consequences for both its chemistry and its quantification.

Its formula is C₂₀₅H₃₄₀N₆₀O₅₃, average mass about 4,493 daltons, CAS 154947-66-7, PubChem CID 16198951. The INN ropocamptide has been assigned to a drug candidate with this sequence. The peptide is amphipathic: when it folds into a helix, hydrophobic residues line up on one face and the cationic residues on the other, which is the structural basis for its interaction with anionic bacterial membranes.

It was predicted from a cDNA clone before it was ever isolated

LL-37 entered the literature as a prediction. In 1995, Agerberth, Gudmundsson and colleagues at Stockholm University reported in the Proceedings of the National Academy of Sciences that a probe designed from the pig PR-39 gene, used to screen a human bone-marrow cDNA library, pulled out eight clones encoding a different putative peptide antibiotic. They named it FALL-39 after its first four residues. The clone encoded a 170-residue cathelin-like precursor; the authors postulated a dibasic processing site, synthesized the predicted 39-mer, and found it active against Escherichia coli and Bacillus megaterium in basal medium E. Circular dichroism showed that medium E induced about 30 percent helix. Unusually for a human antimicrobial peptide, it had no cysteine and no disulfides.

In 1996, Gudmundsson and colleagues reported in the European Journal of Biochemistry the full gene, FALL39: a compact 1,963 base-pair gene with four exons, the first three coding for the signal sequence and cathelin region and the fourth for the mature peptide. They found it to be the only cathelin-family gene in the human genome, located the peptide in granulocytes by immunostaining, and isolated the mature peptide after degranulation. Structural analysis showed the real mature product was LL-37, two residues shorter than the prediction.

The processing step was pinned down by Sørensen and colleagues in Blood in 2001. Using immunoelectron microscopy and immunoblotting of human neutrophils, they showed that hCAP18 was not cleaved inside the phagolysosome after phagocytosis, but was cleaved to LL-37 in exocytosed material, and that of the three azurophil-granule serine proteases, proteinase 3 alone was responsible.

NMR and crystallography show a bent helix that oligomerizes on membranes

The peptide's structure depends on its environment: largely unstructured in water, helical on membranes and in detergent micelles. Wang reported in the Journal of Biological Chemistry in 2008 a triple-resonance NMR structure of ¹³C,¹⁵N-labelled LL-37 in SDS micelles: a curved amphipathic helix-bend-helix spanning residues 2 to 31, with the bend between Gly14 and Glu16 and a disordered C-terminal tail. In dioctanoylphosphatidylglycerol micelles the aromatic rings of Phe5, Phe6, Phe17 and Phe27 and the arginine side chains showed intermolecular NOEs to the lipid, direct evidence that the whole amphipathic helix associates with anionic lipid. The same paper identified KR-12, residues 18 to 29, as the smallest fragment that retained antibacterial activity while sparing human cells in that assay.

Crystallography added the oligomer picture. Sancho-Vaello, Zeth and colleagues reported in Scientific Reports in 2017 a crystal structure showing dimers of antiparallel helices with amphipathic surfaces that remodel when detergent occupies hydrophobic sites at the dimer interface, and electron microscopy of gold-labelled LL-37 on lipid vesicles reproduced fibril-like supramolecular assemblies. In 2020 the same group reported in Scientific Reports that LL-37 crystallized with detergents formed a narrow tetrameric channel with a strongly charged core, that the channel showed small but defined conductance in planar lipid membranes, and that time-lapse imaging of E. coli exposed to the peptide showed outer-membrane discontinuities followed by cell-wall damage. Dürr, Sudheendra and Ramamoorthy's 2006 review in Biochimica et Biophysica Acta remains the standard summary of the biophysics.

What the immunology cell studies measured

Beyond membranes, LL-37 has been shown in human cell assays to act as a chemoattractant through a specific receptor and to change how immune cells respond to DNA. De Yang and colleagues reported in the Journal of Experimental Medicine in 2000 that LL-37 was chemotactic for human peripheral-blood monocytes, neutrophils and T cells, that it induced calcium mobilization in monocytes and in HEK293 cells transfected with formyl peptide receptor-like 1 (FPRL1, now FPR2), and that the monocyte calcium response could be cross-desensitized by an FPRL1-specific agonist.

Lande and colleagues reported in Nature in 2007 that LL-37 was the factor that converted self-DNA into a trigger for plasmacytoid dendritic cells in psoriatic skin. In their cell experiments, the peptide bound DNA into aggregated, condensed complexes that were delivered to and retained in early endosomes, where they activated Toll-like receptor 9 and drove type I interferon production. The 2006 review also catalogues reports of LL-37 binding and neutralizing lipopolysaccharide in vitro. All of these are cell-level findings: receptor engagement, calcium flux, endosomal trafficking and cytokine output measured in human cells. They establish mechanism, not any effect in a person.

Why LL-37 is a standard reagent in microbiology laboratories

LL-37 is the reference human cathelicidin, which makes it the positive control, comparator or probe in an enormous number of antimicrobial-peptide, biofilm and innate-immunity assays. Overhage, Hancock and colleagues reported in Infection and Immunity in 2008 that the peptide inhibited Pseudomonas aeruginosa biofilm formation in vitro at 0.5 µg/mL, far below its minimum inhibitory concentration of 64 µg/mL in the same system, and also affected pre-grown biofilms. Microarray and follow-up work attributed this to reduced attachment, stimulated twitching motility and down-regulation of the Las and Rhl quorum-sensing systems. The mouse peptide CRAMP, despite 67 percent identity, did not share the effect at sub-inhibitory concentrations.

Ridyard and Overhage's 2021 review in Antibiotics lists the reasons LL-37 remains a laboratory tool rather than a product: lower activity in physiological salt and serum, susceptibility to proteolysis, cost, and toxicity to human cells at higher concentrations, along with documented bacterial adaptive responses at sub-inhibitory exposure. For assay design, the practical consequences are that minimum inhibitory concentrations depend heavily on the medium, that the peptide's cationic charge drives adsorption to glass and untreated plastic, and that aggregation at high concentration can change apparent activity. See Why Peptides Stick to Plastic, and How Labs Prevent Adsorption Loss.

Regulatory status: not an approved drug anywhere

LL-37 is not an approved drug in the United States or any other jurisdiction. A European developer carried a synthetic LL-37 candidate under the INN ropocamptide through phase 2 trials for chronic venous leg ulcers; no marketing authorization has resulted. In the United States, FDA placed LL-37 in Category 2 of its list of bulk drug substances nominated for use in compounding under section 503A, the category for substances the agency has identified as raising significant safety risks, in its 2023 updates. A research vial is supplied for in vitro assays such as those described above and is not a pharmaceutical product. For the broader status picture across the catalog, see FDA Status of Common Research Peptides: A Reference Table.

What a certificate should show for a cationic peptide with no UV chromophore

Two features of LL-37 change how its certificate should be read: it absorbs almost nothing at 280 nm, and it carries up to eleven counter-ions. With no tryptophan or tyrosine, absorbance at 280 nm cannot be used for content, so net peptide content must come from amino acid analysis, nitrogen determination or absorbance at 205 to 214 nm with a stated method. A certificate that reports content "by UV" without specifying the wavelength or method is not informative for this sequence. See Net Peptide Content vs Purity.

Because the peptide has eleven basic side chains plus the N-terminus, a trifluoroacetate salt can carry a substantial mass of TFA, and trifluoroacetate is known to affect some cell-based assays; the counter-ion should be declared, and an acetate exchange is often preferred for cell work. See TFA Salt vs Acetate Salt: Why the Counter-Ion on a Peptide Matters. On the positive side, the absence of cysteine and methionine removes the two most common oxidation pathways, so the HPLC trace should be relatively clean; the likely impurities are deletion sequences from a 37-step synthesis, which mass spectrometry resolves easily since each missing residue shifts the mass by a known amount. Identity by mass spectrometry should show an observed average mass near 4,493 daltons, typically across +4 to +7 charge states.

US Prime Peptides posts lot-matched certificates before purchase for LL-37 5 mg and LL-37 10 mg, each covering identity by mass spectrometry, HPLC purity, net peptide content, endotoxin, sterility and heavy metals, with an independent third-party report. For a peptide used in endotoxin-sensitive immunology assays, the endotoxin line deserves particular attention.

Frequently Asked Questions

What does LL-37 stand for?

The name describes the peptide: it begins with two leucines (LL) and is 37 residues long. It is the mature C-terminal fragment of hCAP18, the only human cathelicidin, isolated from granulocytes in 1996 after being predicted as the slightly longer FALL-39 in 1995.

How does LL-37 interact with bacterial membranes?

NMR shows it forms a bent amphipathic helix on anionic lipid surfaces, with phenylalanine and arginine side chains contacting the lipid. Crystal structures show antiparallel dimers, fibril-like assemblies and a tetrameric channel in detergent, and imaging of exposed E. coli shows outer-membrane disruption followed by cell-wall damage.

Is LL-37 an approved drug?

No. An LL-37 candidate (INN ropocamptide) completed phase 2 trials in Europe without approval, and FDA placed LL-37 in Category 2 of its 503A bulk substances list in 2023. Research vials are for in vitro assays only.

Why can't LL-37 content be measured by absorbance at 280 nm?

The sequence has no tryptophan or tyrosine, the residues that absorb at 280 nm, so a 280 nm reading is close to zero regardless of how much peptide is present. Content has to be measured by amino acid analysis, nitrogen content or far-UV absorbance near 214 nm with a stated method.

Citations

1. Agerberth B, Gunne H, Odeberg J, Kogner P, Boman HG, Gudmundsson GH. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc Natl Acad Sci USA. 1995;92:195-199. PMID 7529412
2. Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur J Biochem. 1996;238:325-332. PMID 8681941
3. De Yang, Chen Q, Schmidt AP, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med. 2000;192:1069-1074. PMID 11015447
4. Sørensen OE, Follin P, Johnsen AH, et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97:3951-3959. PMID 11389039
5. Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758:1408-1425. PMID 16716248
6. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564-569. PMID 17873860
7. Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 2008;76:4176-4182. PMID 18591225
8. Wang G. Structures of human host defense cathelicidin LL-37 and its smallest antimicrobial peptide KR-12 in lipid micelles. J Biol Chem. 2008;283:32637-32643. PMID 18818205
9. Sancho-Vaello E, François P, Bonetti EJ, et al. Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species. Sci Rep. 2017;7:15371. PMID 29133814
10. Sancho-Vaello E, Gil-Carton D, François P, et al. The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics. Sci Rep. 2020;10:17356. PMID 33060695
11. Ridyard KE, Overhage J. The potential of human peptide LL-37 as an antimicrobial and anti-biofilm agent. Antibiotics (Basel). 2021;10:650. PMID 34072318

This article is for laboratory research reference only. US Prime Peptides products are supplied strictly for in vitro research. Not for human consumption.

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