Cathelicidin-derived cationic antimicrobial and immunomodulatory peptide
The sole human cathelicidin-derived antimicrobial peptide, a 37-residue amphipathic alpha-helical cationic peptide released from the precursor protein hCAP-18 by proteinase 3 cleavage, possessing direct broad-spectrum antimicrobial activity through membrane disruption and pleiotropic immunomodulatory functions mediated by formyl peptide receptor 2, P2X7, and toll-like receptor signaling.
Abstract
LL-37, the carboxy-terminal 37-residue peptide of human cationic antimicrobial protein 18 (hCAP-18), is the only cathelicidin-derived antimicrobial peptide identified in the human genome and is a central effector of innate immune defense across epithelial surfaces, wound repair, and inflammatory regulation. The peptide was first identified as FALL-39 by Gudmundsson, Agerberth, and colleagues at the Karolinska Institutet in 1996 through screening of a human bone marrow cDNA library [1], and the mature processed form was subsequently designated LL-37 on the basis of its amino-terminal leucine-leucine sequence and 37-residue length [2]. hCAP-18, the 18-kilodalton holoprotein precursor, is constitutively stored in the specific granules of neutrophils and is released and proteolytically processed by neutrophil-derived proteinase 3 at sites of infection and inflammation to yield the biologically active LL-37 fragment [3]. The peptide adopts an amphipathic alpha-helical conformation in membrane-mimetic environments and exerts direct antimicrobial activity against gram-positive and gram-negative bacteria, enveloped viruses, and fungi through electrostatic interaction with anionic microbial membranes followed by membrane permeabilization and disruption [4, 5]. Beyond direct microbicidal activity, LL-37 functions as a multifunctional immunomodulatory mediator: it signals through formyl peptide receptor 2 (FPR2/ALX) to recruit neutrophils, monocytes, and T cells [6]; it neutralizes bacterial lipopolysaccharide and prevents endotoxin-driven inflammatory cascades [7]; it promotes angiogenesis and wound re-epithelialization through epidermal growth factor receptor transactivation [8]; and it modulates adaptive immune responses through effects on dendritic cell maturation and T helper cell polarization [9]. Expression of hCAP-18/LL-37 is transcriptionally regulated by 1,25-dihydroxyvitamin D3 through a vitamin D response element in the CAMP gene promoter, a mechanism first characterized by Liu et al. (2006) in a landmark demonstration that toll-like receptor activation of human macrophages by Mycobacterium tuberculosis triggers CYP27B1-mediated conversion of 25-hydroxyvitamin D to the active 1,25-dihydroxy form, which then induces cathelicidin expression and intracellular killing of the mycobacterium [10]. This vitamin D-cathelicidin axis has become a major research focus in tuberculosis, respiratory infection, and immunodeficiency. Clinical translation of LL-37 has advanced through Phase I and Phase II trials in chronic wound healing, where topical application of synthetic LL-37 at 0.5 and 1.6 mg/mL produced healing rate constants approximately three- to six-fold greater than placebo in hard-to-heal venous leg ulcers [11], and through a Phase IIb multicenter trial of 148 patients that identified a subgroup benefit in ulcers exceeding 10 cm2 [12]. A randomized trial of recombinant LL-37 delivered via Lactococcus lactis as oral therapy against SARS-CoV-2 Omicron BA.5.1.3 demonstrated significant shortening of viral RNA negative conversion time with early intervention and acceptable safety [13]. The peptide is also implicated in the pathogenesis of rosacea, where aberrant processing of cathelicidin by kallikrein 5 serine protease generates proinflammatory LL-37 fragments in facial skin [14]; in psoriasis, where LL-37 complexed with self-DNA activates plasmacytoid dendritic cells through toll-like receptor 9 [15]; and in cancer biology, where context-dependent pro-tumorigenic and anti-tumorigenic effects have been reported across colorectal, breast, ovarian, and lung malignancies [16, 17]. Pharmacokinetically, the peptide is susceptible to rapid proteolytic degradation in serum with a half-life of minutes to hours depending on protease milieu, limiting systemic bioavailability and driving research toward local and topical delivery, protease-resistant analogs, d-amino acid substitutions, and nanoparticle encapsulation strategies [18, 19]. The compound is commercially available as a synthetic peptide at greater than 95 percent purity from multiple peptide synthesis suppliers. This monograph reviews the chemistry, structure, and processing of LL-37; the molecular pharmacology including direct antimicrobial mechanisms and immunomodulatory receptor signaling; the vitamin D transcriptional axis; preclinical pharmacology across infection, inflammation, and wound healing models; the clinical evidence base in chronic wounds, infectious disease, and dermatologic conditions; reconstitution and handling; stack interactions; adverse events and safety signals including the rosacea and psoriasis pathogenic associations; and a comparative assessment of five alternative antimicrobial and immunomodulatory peptide candidates against LL-37 on five competency standards.
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