Peerless Peptides

LL-37

Endogenous human cathelicidin α-helical antimicrobial peptide, 37 amino acids

LL-37 is the 37-residue α-helical cationic antimicrobial peptide cleaved from the C-terminus of the human cathelicidin precursor hCAP-18 (CAMP gene, UniProt P49913). Identified independently in 1995 by Agerberth et al. (Stockholm) and Cowland, Johnsen, and Borregaard at the Rigshospitalet Granulocyte Research Laboratory, it is the only known human cathelicidin. The published preclinical literature includes a dual-role-in-cancer body of work spanning pro-tumorigenic reports in breast, lung, and pancreatic models against anti-tumorigenic reports in colon and gastric models. The most-developed clinical asset (Promore Pharma ropocamptide) missed its Phase 2b primary endpoint in 2021.

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Biochemical Profile

CAS Number
154947-66-7
Molecular Formula
C205H340N60O53
Molecular Weight
4493.34 g/mol
Purity
≥98% (HPLC-UV (214-220 nm))
PubChem CID
16198951
Amino Acid Sequence
LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES

Receptor Targets and Signaling Pathway Context

LL-37 has been characterized as a multi-functional innate-immunity effector with three distinct biological activities described in the primary literature: direct antimicrobial membrane disruption, bacterial lipopolysaccharide (LPS) neutralization, and immunomodulation via several host-cell receptors. The peptide is stored as the 18 kDa hCAP-18 precursor in neutrophil specific granules and is released by proteinase 3 cleavage following degranulation, an extracellular event established by the Borregaard group in 2001[1].

The dominant antimicrobial mechanism is membrane disruption. The cationic peptide binds anionic membrane components (LPS in Gram-negative outer membranes, lipoteichoic acid and acidic phospholipids in Gram-positive membranes), transitions from random coil to amphipathic α-helix on the membrane surface, and at threshold local concentrations induces curvature stress and transient pore formation in a carpet orientation parallel to the bilayer. Activity has been reported against Gram-positive and Gram-negative bacteria, fungi, and enveloped viruses, though MIC values are markedly reduced in physiological salt concentrations, a long-recognized translational limitation of cationic antimicrobial peptides[2].

LL-37 binds bacterial LPS with sub-micromolar affinity via interactions between cationic lysine and arginine residues and the anionic lipid A and core polysaccharide regions. Bound LPS is sequestered from TLR4-MD2 signaling, and the resulting reduction in TNF-α, IL-1β, and IL-6 release from LPS-stimulated monocytes and macrophages is the basis for the separate sepsis-protective characterization of the peptide.

The immunomodulatory pharmacology is characterized as receptor-pluripotent. LL-37 has been reported as a ligand or modulator for FPR2 (formyl peptide receptor 2, the chemotaxis and angiogenesis receptor characterized by De Yang 2000 and Koczulla 2003)[3], P2X7 (a purinergic receptor on macrophages and T cells implicated in NLRP3 inflammasome modulation), EGFR (transactivation on epithelial cells and keratinocytes, von Haussen 2008), IGF-1R (a partial-agonist β-arrestin-1-dependent MAPK/ERK pathway characterized by Girnita 2012), and TLR9 on plasmacytoid dendritic cells via LL-37-self-DNA complexes (Lande 2007, the psoriasis-pathology mechanism)[4]. Because LL-37 binds multiple receptors with overlapping signaling outputs, the net effect on a given cell type depends on which receptor combinations that cell expresses and at what density. This receptor-combinatorics framework is the leading hypothesis for the dual-role-in-cancer phenomenon described elsewhere on this page.

LL-37 is membrane-active. The same property that drives antimicrobial activity drives concentration-dependent cytotoxicity against host cells at higher exposure levels, including erythrocyte hemolysis and lysis of human vascular smooth muscle cells documented at 6 to 20 µM. Plasma apoA-I binding and the globular C1q receptor (p33) provide partial endogenous sequestration of the cationic peptide, but the protective margin is saturable[5]. Pharmacokinetic data in humans are limited to topical formulations from the Promore Pharma program; systemic LL-37 pharmacokinetics have not been definitively established in the peer-reviewed clinical literature.

Research Applications

Antimicrobial and Anti-Infective Research

Antimicrobial-activity preparations are the foundational application area in the LL-37 literature, with reported in vitro activity against most clinical bacterial pathogens including Staphylococcus aureus (including MRSA strains), Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Streptococcus pyogenes, and Mycobacterium tuberculosis. Activity against enveloped viruses (HIV-1, influenza A, respiratory syncytial virus, SARS-CoV-2 by molecular-simulation and in vitro studies) and fungi (Candida albicans) has also been documented[2].

A recurring translational obstacle reported across the cationic antimicrobial peptide literature is salt-sensitivity. MIC values for LL-37 are markedly higher in physiological saline than in low-salt buffer, a feature shared with most α-helical cationic antimicrobial peptides. In cystic fibrosis airway secretions, LL-37 antimicrobial activity is further reduced because the peptide binds DNA and F-actin in the sputum matrix; this finding informs the rationale for inhaled DNase co-administration in CF airway clearance regimens.

No published prospective interventional human trial of LL-37 in any infectious-disease indication has been completed as of May 2026.

Wound and Skin Research

Re-epithelialization preparations have been a sustained focus across the LL-37 literature. Heilborn et al. (J Invest Dermatol 2003, PMID 12603850) reported the paper titled 'The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium'[6]. The authors demonstrated that hCAP-18 expression peaks 48 hours post-injury in healing human skin, is detected in inflammatory infiltrate and migrating epithelium, and is absent or markedly reduced in chronic ulcer epithelium; affinity-purified antibodies against LL-37 inhibited re-epithelialization in an ex vivo organ-cultured human skin model in a concentration-dependent manner. This 2003 paper is the foundational rationale for therapeutic LL-37 supplementation in chronic wounds.

The most-developed clinical asset is the Lipopeptide AB / Promore Pharma AB ropocamptide program in venous leg ulcers. A 34-patient Phase 2a (Grönberg et al. 2014) reported an inverted dose-dependent pattern in which the low 0.5 milligrams per milliliter arm displayed a healing rate constant approximately 6-fold higher than placebo (p=0.003), the 1.6 milligrams per milliliter arm approximately 3-fold higher (p=0.088), and the 3.2 milligrams per milliliter arm no significant effect over placebo[7]. The larger 148-patient Phase 2b trial (Mahlapuu et al. 2021, EudraCT 2018-000536-10) missed its primary endpoint of complete confirmed wound closure in the overall population (26.5 percent, 24.7 percent, and 25.3 percent across groups, all p greater than 0.05); a post-hoc subgroup analysis in ulcers of at least 10 cm² reported a statistically significant benefit at the 0.5 milligrams per milliliter dose (28.1 percent versus placebo 8.1 percent, p=0.0458)[8]. The program has not advanced beyond Phase 2b.

A separate investigator-initiated Phase 2 trial of LL-37 cream in diabetic foot ulcer (Miranda et al. 2023, Universitas Indonesia) reported a faster granulation index in the LL-37 group at days 7, 14, 21, and 28; the study did not report statistically significant decreases in IL-1α, TNF-α, or aerobic bacterial colonization at trial end[9].

Dermatology: Psoriasis and Rosacea Research

LL-37 occupies a paradoxical position in inflammatory skin disease. The same peptide reported as necessary for normal wound re-epithelialization has also been characterized as a driver of two distinct cutaneous inflammatory pathologies in the published literature.

In psoriasis, plasmacytoid dendritic cells infiltrating psoriatic skin lesions are activated by LL-37 complexed with self-DNA released from dying keratinocytes. The LL-37-self-DNA complex binds TLR9 on plasmacytoid dendritic cells and triggers type I interferon (IFN-α) production. The Lande 2007 Nature paper is the paradigm-setting reference; keratinocytes in psoriatic lesions overexpress both LL-37 and TLR9[4]. Lande and colleagues subsequently extended the mechanism into systemic lupus erythematosus, characterizing LL-37-self-DNA complexes externalized by NETosing neutrophils as drivers of plasmacytoid-dendritic-cell-mediated type I interferon production. Circulating autoantibodies against LL-37 have been reported in SLE patient sera and form a feed-forward loop with further NET formation.

In rosacea, the pathology arises not from LL-37 overexpression but from aberrant processing. Yamasaki et al. 2007 reported that increased kallikrein 5 serine-protease activity in rosacea-affected skin cleaves hCAP-18 into peptide fragments that drive inflammation, erythema, and telangiectasia[10]. The cathelicidin-driven rosacea model is now an established skin-biology paradigm.

Angiogenesis and Vascular Research

Koczulla et al. 2003 established LL-37 as a direct angiogenic peptide in the published literature. The paper used Matrigel plug assays, hindlimb ischemia models, and aortic ring sprouting assays. The proposed receptor was FPR2 on endothelial cells; the angiogenic activity was reported to be independent of antimicrobial activity[3]. This finding has been replicated across multiple independent groups and is the foundation for the wound-healing development rationale used in the Promore Pharma program (the hypothesis that LL-37 accelerates chronic wound closure by both clearing bacterial burden and stimulating neovascularization).

Mechanistically, the FPR2 chemotaxis signal extends to neutrophils, monocytes, T cells, mast cells, and endothelial cells, with downstream effects including chemotaxis, anti-apoptotic signaling, and EGFR transactivation in epithelial cells (von Haussen 2008). The IGF-1R interaction (Girnita 2012) was reported as β-arrestin-1-dependent partial agonism rather than orthosteric binding, with downstream MAPK/ERK activation. The structural basis for the angiogenic activity remains under investigation; the LL-37 NMR structure in dodecylphosphocholine micelles (PDB 2K6O, Porcelli et al. 2008) shows an amphipathic helix-bend-helix motif spanning residues 2 to 31 with a flexible C-terminal tail.

Cancer Biology: Dual-Role Literature

The cancer-biology literature on LL-37 is the most editorially distinctive area of the cathelicidin field because the reported effects on tumor cells differ in direction depending on tumor type, expression context, and concentration. Pro-tumorigenic effects have been reported in breast cancer (Heilborn et al. 2005 characterized hCAP-18/LL-37 as highly expressed in breast cancer tissue compared to normal breast and as a putative growth factor for epithelial cells)[11]; in ovarian cancer (Coffelt and colleagues reported FPR2-mediated mesenchymal stromal cell recruitment); in lung cancer (von Haussen 2008 reported EGFR-phosphorylation-driven proliferation at low LL-37 concentrations); in pancreatic cancer (multiple reports of FPR2- and P2X7-mediated cancer stem cell invasion and self-renewal); in melanoma (Chen et al. 2023 reported a translational follow-up characterizing LL-37 activation of melanoma cells and tumor-associated macrophages)[12]; and in hepatocellular carcinoma. Anti-tumorigenic effects have been reported in colon cancer (Ren et al. 2012 characterized caspase-independent apoptosis induction in colon cancer xenografts, with LL-37 expression down-regulated in colon cancer relative to normal colon epithelium); in gastric cancer; and in certain hematologic contexts.

The published review literature has explicitly acknowledged the contradiction. Wu et al. (Archivum Immunologiae et Therapiae Experimentalis 2016) concluded that at this point it is not possible to make an indisputable judgment on the effect of LL-37 on cancer development[13]. The hypothesized resolution is receptor-combinatorics: LL-37 binds at least four host receptors (FPR2, P2X7, EGFR, IGF-1R) and the net effect on a tumor cell depends on which receptors are expressed and at what density. The contradiction has not been definitively resolved for any specific tumor type, and the safety implications for any systemic administration program remain unestablished.

Replication and Clinical Status

The LL-37 literature comprises approximately 3,500 PubMed-indexed papers through May 2026, a substantially larger corpus than for any other peptide in this category. The biology is well-characterized: the biochemistry, NMR structure, antimicrobial activity, LPS neutralization, and receptor pharmacology have been independently replicated across multiple labs over three decades. Mouse CRAMP knockout (Cnlp negative-slash-negative) studies have established LL-37 as a load-bearing component of host defense.

The clinical evidence does not yet support a defined therapeutic application. The Lipopeptide AB / Promore Pharma AB ropocamptide program in venous leg ulcers is the most-developed clinical asset. The 34-patient Phase 2a (Grönberg 2014, PMID 25231515) was positive on healing rate constant at the low 0.5 milligrams per milliliter arm; the larger 148-patient Phase 2b trial (Mahlapuu 2021, PMID 34687253) missed its primary endpoint in the overall population. Both trials reported an inverted dose-dependent pattern in which the lower 0.5 milligrams per milliliter dose outperformed the higher 1.6 or 3.2 milligrams per milliliter doses, a finding consistent with the proposition that clinical doses approach the upper boundary of the LL-37 therapeutic window in wound exudate. Promore Pharma AB announced a reverse acquisition of PMD Device Solutions AB (an Irish respiratory medical-device company) on November 29, 2023; the reverse merger was completed in January 2024 and the LL-37 program has not progressed under the renamed entity, with the focus now on respiratory monitoring devices rather than peptide therapeutics[14].

A separate Phase 1 trial of intratumoral LL-37 in melanoma (NCT02225366, MD Anderson Cancer Center) completed with unexpected dermatologic toxicity (Liu et al. 2018) and translational follow-up suggesting LL-37 might contribute to local invasion (Chen 2023, PMID 36981094)[15][12]. The intratumoral melanoma indication has not advanced to Phase 2. As of May 2026, no active US-, EU-, or Japan-based industry developer is pursuing Phase 3 of LL-37 in any indication.

The regulatory status as of May 2026: FDA removed LL-37 from 503A Category 2 (Do-Not-Compound) effective April 22, 2026. Removal does not confer Category 1 status or compoundability. The Pharmacy Compounding Advisory Committee (PCAC) has scheduled a separate consultation on LL-37 before the end of February 2027, deferred from the July 23, 2026 cohort that included BPC-157, TB-500, MOTS-c, Epitalon, KPV, and Semax[16]. LL-37 is not on the WADA 2026 Prohibited List. LL-37 was named in the 2021 Tailor Made Compounding LLC plea agreement (alongside BPC-157, CJC-1295, Ipamorelin, Selank, Semax, and others).

Reconstitution & Storage

Recommended Diluent
Bacteriostatic water (0.9% benzyl alcohol)
Storage (lyophilized)
-20°C, dry, dark, 24+ months
Storage (reconstituted)
2-8°C, use within 14-28 days; low-binding or siliconized vials preferred
Shelf Life
24+ months lyophilized

Research References

  1. [1] Sørensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, Borregaard N. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97(12):3951-3959. PMID:11389039
  2. [2] Cowland JB, Johnsen AH, Borregaard N. hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules. FEBS Lett. 1995;368(1):173-176. PMID:7615076
  3. [3] Koczulla R, von Degenfeld G, Kupatt C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111(11):1665-1672. doi:10.1172/JCI17545PMID:12782669
  4. [4] Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564-569. PMID:17873860
  5. [5] 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(1):195-199. PMID:7529412
  6. [6] Heilborn JD, Nilsson MF, Kratz G, Weber G, Sorensen O, Borregaard N, Stahle-Backdahl M. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol. 2003;120(3):379-389. PMID:12603850
  7. [7] Grönberg A, Mahlapuu M, Ståhle M, Whately-Smith C, Rollman O. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen. 2014;22(5):613-621. PMID:25231515
  8. [8] Mahlapuu M, Sidorowicz A, Mikosinski J, et al. Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: a multicentric prospective randomized placebo-controlled clinical trial. Wound Repair Regen. 2021;29(6):938-950. PMID:34687253
  9. [9] Miranda E, Bramono K, Yunir E, et al. Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. Arch Dermatol Res. 2023. PMID:37480520
  10. [10] Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-980. PMID:17676051
  11. [11] Heilborn JD, Nilsson MF, Jimenez CIC, et al. Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer. 2005;114(5):713-719. PMID:15609302
  12. [12] Chen X, Liu W, Wang Y, et al. LL-37 might promote local invasion of melanoma by activating melanoma cells and tumor-associated macrophages. 2023. PMID:36981094
  13. [13] Wu WK, Wang G, Coffelt SB, et al. The role of cathelicidin LL-37 in cancer development. Arch Immunol Ther Exp. 2016. PMID:26395996
  14. [14] Promore Pharma AB. Notice of reverse acquisition of PMD Device Solutions AB. Press release November 29, 2023; merger completed January 2024. Combined entity renamed PMD Device Solutions AB; LL-37 / ropocamptide development program dormant under new corporate scope.
  15. [15] Liu Z, Yang X, Tian Z, et al. Dermatologic toxicity from novel therapy using antimicrobial peptide LL-37 in melanoma: a detailed examination of the clinicopathologic features. J Am Acad Dermatol. 2018. PMID:29665030
  16. [16] US Food and Drug Administration. 503A Bulks List reclassification notice, April 15, 2026 (effective April 22, 2026); LL-37 removed from Category 2 with separate Pharmacy Compounding Advisory Committee consultation scheduled before end of February 2027, deferred from July 23, 2026 cohort.
  17. [17] 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(7):1069-1074. PMID:11015447
  18. [18] Cowland JB. Niels Borregaard, M.D. (1951-2017). J Leukoc Biol. 2017. PMID:28468984

Scientific Journal Author

Niels Borregaard, MD, DMSc (1951-2017)

Department of Hematology, Rigshospitalet, University of Copenhagen

Landmark Publications

  • Cowland JB, Johnsen AH, Borregaard N. hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules. FEBS Lett. 1995;368(1):173-176. (PMID 7615076)
  • Sørensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, Borregaard N. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97(12):3951-3959. (PMID 11389039)
  • Cowland JB. Niels Borregaard, M.D. (1951-2017). J Leukoc Biol. 2017. (PMID 28468984)

Dr. Niels Borregaard (1951 to 2017), Professor of Hematology at the University of Copenhagen and founder of the Granulocyte Research Laboratory at Rigshospitalet, is independently cited here as the senior co-identifier of hCAP-18 (1995) and the senior author of the canonical paper establishing proteinase 3 as the extracellular processing enzyme that releases LL-37 from hCAP-18 (Blood 2001). Dr. Borregaard died of lung cancer on January 10, 2017. There is no affiliation or commercial relationship between the Borregaard estate, the University of Copenhagen, Rigshospitalet, or any associated entity, and Peerless Peptides.

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