LL-37 is the only human antimicrobial peptide and is a 37 amino acid peptide derived from the C-terminal domain of its precursor protein hCAP-18 (human cationic antimicrobial protein 18). It plays a key role in innate immunity and exhibits broad-spectrum antimicrobial activity against bacteria, fungi and viruses. In addition to its antimicrobial function, LL-37 is involved in immune regulation, wound healing, angiogenesis and cancer regulation.Its expression is ubiquitous on neutrophils, epithelial cells and mucosal surfaces (e.g. vagina and skin), where it serves as a first line of defense against pathogens. Notably, its activity is regulated by proteolytic processing (e.g. by serine proteases) and environmental factors such as vitamin D.
Structural and Physicochemical Properties
LL-37, Antimicrobial Peptide:
Single letter code: LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES
Triple letter code:
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
Molecular weight: 4493.33
Adopts an amphipathic α-helix with three domains:
terminal: Mediates chemotaxis and hemolytic activity.
C-terminal: Responsible for membrane disruption and antiviral activity.
C-terminal tail: Facilitates tetramerization via interactions with anionic biomolecules.
Stability and Charge Dynamics
Charge: Net +6 at physiological pH enables electrostatic targeting of microbial membranes.
Thermal stability: Fibrillar self-assembly of fragments (e.g., LL-37(17–29)) resists degradation at 60–80°C.
Protease resistance: Hydrophobic packing and polar interactions confer partial resistance to host proteases.
Synthesis Route
Chemical Synthesis:
Solid-phase peptide synthesis (SPPS) is commonly used for producing LL-37 and its fragments (e.g., LL-37(17–29)) .
Advantages: High purity, flexibility for structural modifications (e.g., mutagenesis for functional studies).
Challenges: High cost for large-scale production and potential misfolding issues.
Recombinant Expression:
Prokaryotic systems (e.g., E. coli) are used for LL-37 production, requiring codon optimization and fusion tags to avoid toxicity.
Advantages: Cost-effective for bulk production.
Challenges: Post-translational modifications (e.g., cleavage from fusion tags) and potential inclusion body formation.
Biomimetic Self-Assembly:
LL-37 fragments (e.g., LL-37(17–29)) self-assemble into functional fibrils, offering a scaffold for stable biomaterials .
Advantages: Enhances antimicrobial efficacy and stability.
Challenges: Controlling assembly dynamics for therapeutic consistency.
Applications and Significance
Antimicrobial Therapy:
LL-37 effectively reduces fungal burdens (e.g., Candida albicans in vulvovaginal candidiasis) and bacterial infections by disrupting membranes and modulating cytokines (e.g., increasing IFN-γ and reducing IL-10) .
Cancer Modulation:
Exhibits dual roles: anti-cancer (e.g., inhibiting hepatocellular carcinoma proliferation via transcriptomic regulation ) and pro-tumorigenic effects (e.g., promoting skin squamous cell carcinoma via NF-κB/dbpA signaling) .
Chronic Diseases:
Low plasma LL-37 levels correlate with frequent exacerbations in COPD patients, highlighting its role in immune defense and vitamin D interplay .
Biomaterials and Drug Delivery:
Self-assembled LL-37 fibrils show potential for durable antimicrobial coatings and drug carriers due to their stability and surface charge (+25 mV) .
Current Challenges
Dual functionality: Context-dependent pro-/anti-tumor effects complicate therapeutic targeting.
Synthesis limitations: SPPS and recombinant systems struggle with cost and yield.
Immunotoxicity: Overactivation of immune pathways (e.g., in asthma) risks adverse inflammation.
Future Perspectives
Peptide Engineering: Develop cancer-selective mutants (e.g., EGFR-binding domain truncations).
Nanocarrier Systems: Utilize self-assembled fibrils for controlled drug release.
Clinical Trials: Prioritize dose-escalation studies in biofilm-related infections and autoimmune diseases .
LL-37 exemplifies the convergence of innate immunity and therapeutic innovation. While its antimicrobial and immunomodulatory properties hold clinical promise, challenges in synthesis, selectivity, and safety demand interdisciplinary solutions. Future advances hinge on structural optimization, biomarker-guided delivery, and translational validation.
References
1. Human antimicrobial peptide, LL-37, induces non-inheritable reduced susceptibility to vancomycin in Staphylococcus aureus. Scientific Reports (2025).
2. LL-37 Antimicrobial Peptide, human. 药智通 (2024).
3. LL-37, antimicrobial peptide, human. ChemicalBook (2024).
4. LL-37 promotes skin squamous cell carcinoma via NF-κB/dbpA. Oncology Letters (2016).
5. LL-37 derivatives with vancomycin against S. aureus. J. Antibiotics (2025).
6. LL-37 eradicates S. aureus biofilms. PLOS ONE (2019).
7. LL-37 in asthma exacerbation. Scientific Reports (2017).
8. LL-37 in autoimmunity and viral infections. Vaccines (2020).
9. The Anticancer Mechanism of Human Antimicrobial Peptide LL-37. Aqeel Ahmad[1], Mohammed Ali Mullah Fawaz[2]. DOI: 10.37881/1.63.
