LL-37

Overview

LL-37 is the only human cathelicidin antimicrobial peptide, a 37-amino acid peptide derived from the C-terminus of the 18 kDa human cationic antimicrobial protein (hCAP18). It is a critical component of the innate immune system and represents the body's first line of defense against microbial invasion.

The name "LL-37" refers to its two leucine (L) residues at the N-terminus and its length of 37 amino acids. It is produced by various cells including neutrophils, macrophages, and epithelial cells throughout the body.

Key Characteristics

• Origin: Naturally occurring human antimicrobial peptide
• Classification: Cathelicidin / Host defense peptide
• Length: 37 amino acids
• Charge: +6 at physiological pH (cationic)
• Unique Feature: Only human cathelicidin, broad-spectrum activity

Functions Overview

| Function | Description | |----------|-------------| | Antimicrobial | Direct killing of bacteria, viruses, fungi | | Immunomodulation | Regulates immune cell responses | | Wound Healing | Promotes tissue repair | | Anti-Biofilm | Disrupts bacterial biofilms | | Anti-Inflammatory | Modulates inflammatory responses |

Mechanism

Primary Mechanisms

1. Membrane Disruption (Antimicrobial)

LL-37 kills microbes through:

• Binding to negatively charged microbial membranes
• Forming pores or carpet-like coverage
• Disrupting membrane integrity
• Causing microbial cell death
• Selectivity for microbial vs human membranes

2. Immunomodulation

Effects on immune cells:

• Chemotaxis of immune cells to infection sites
• Modulation of cytokine production
• Enhancement of phagocytosis
• Regulation of inflammatory responses
• Activation of innate immune pathways

3. Anti-Biofilm Activity

Against biofilm infections:

• Prevents biofilm formation
• Disrupts established biofilms
• Enhances antibiotic penetration
• Important for chronic infections

4. Wound Healing

Tissue repair effects:

• Promotes keratinocyte migration
• Stimulates angiogenesis
• Modulates epithelial cell proliferation
• Balances inflammation during healing

Receptor Interactions

LL-37 interacts with multiple receptors:

• FPRL1/FPR2: G-protein coupled receptor, chemotaxis
• P2X7: ATP-gated ion channel, inflammation
• TLRs: Toll-like receptors, immune signaling
• EGFR: Epidermal growth factor receptor, wound healing

Research

Antimicrobial Activity

Bacterial Pathogens

LL-37 shows activity against:

• Gram-positive: S. aureus, Streptococcus, Enterococcus
• Gram-negative: E. coli, P. aeruginosa, Klebsiella
• Mycobacteria: M. tuberculosis
• Drug-resistant strains: MRSA, VRE, MDR bacteria

Viral Activity

Research indicates effectiveness against:

• Enveloped viruses (HSV, HIV, influenza)
• Respiratory viruses
• Coronaviruses (emerging research)
• Mechanism: membrane disruption, entry inhibition

Antifungal

Studies show activity against:

• Candida species
• Aspergillus
• Biofilm-forming fungi

Clinical Applications Research

Chronic Wounds

Research in wound healing:

• Diabetic ulcer studies
• Pressure wound investigations
• Burn healing applications
• Chronic wound management

Respiratory Infections

Pulmonary applications:

• Cystic fibrosis (CF lung infections)
• Chronic sinusitis
• Respiratory tract infections
• Biofilm-associated infections

Skin Conditions

Dermatological research:

• Rosacea (dysregulated in this condition)
• Psoriasis
• Atopic dermatitis
• Wound infections

Biofilm Research

Clinical Significance

Biofilm infections are notoriously difficult:

• 80% of chronic infections involve biofilms
• LL-37 can prevent and disrupt biofilms
• Synergizes with conventional antibiotics
• Potential for catheter-associated infections

Dosing

Research Protocols

Administration Routes

Subcutaneous Injection

• Most common for systemic effects
• Rapid absorption
• Rotate injection sites
• Standard sterile technique

Topical Application

• For wound healing applications
• Can be formulated in gels or creams
• Applied directly to affected area
• May require compounding

Intranasal

• For sinus/respiratory applications
• Delivered via nasal spray
• Local antimicrobial effect
• Experimental approach

Reconstitution

• Reconstitute with bacteriostatic water
• Store refrigerated after reconstitution
• Protect from light
• Limited stability data - use promptly
• Some degradation expected over time

Pharmacokinetics

Absorption

• Subcutaneous: Well absorbed
• Topical: Local absorption, limited systemic
• Intranasal: Mucosal absorption

Distribution

• Concentrates at sites of infection/inflammation
• Present in various body fluids naturally
• Tissue penetration variable

Metabolism

• Degraded by proteases
• Can be inactivated in certain environments
• Modified forms may have improved stability

Elimination

• Relatively rapid clearance
• Half-life varies by tissue and context
• No accumulation with standard dosing

Synergy & Stacking

Common Combinations

LL-37 + Conventional Antibiotics

Synergistic antimicrobial effects:

• LL-37 disrupts biofilms, enhances antibiotic access
• Reduces required antibiotic doses
• May overcome some resistance mechanisms
• Particularly useful for chronic infections

LL-37 + BPC-157

Healing and antimicrobial:

• BPC-157: Tissue healing
• LL-37: Infection prevention
• Comprehensive wound management
• Complementary mechanisms

LL-37 + Thymosin Alpha-1

Immune enhancement:

• Thymosin Alpha-1: Adaptive immunity
• LL-37: Innate immunity
• Comprehensive immune support
• For immune-compromised states

Potential Conflicts

• Certain salts may reduce LL-37 activity
• Serum proteins can partially inhibit
• Acidic environments may affect stability
• Consider formulation carefully

Safety

Known Side Effects

Common

• Injection site reactions (redness, swelling)
• Local irritation (topical use)
• Mild inflammation at site

Potential Concerns

• Pro-inflammatory in certain contexts
• May exacerbate some autoimmune conditions
• Possible mast cell activation

Paradoxical Effects

LL-37 Dysregulation in Disease

LL-37 is abnormally elevated in:

• Rosacea: Overproduction contributes to inflammation
• Psoriasis: Elevated in psoriatic lesions
• Atherosclerosis: Found in plaques

This highlights that balance is important - neither deficiency nor excess is ideal.

Contraindications

Avoid or use with extreme caution if:

• Rosacea (may worsen)
• Certain autoimmune conditions
• Mast cell disorders
• History of severe allergic reactions

Drug Interactions

• May interact with immunosuppressants
• Potential synergy with antibiotics (beneficial)
• Caution with drugs affecting immune function
• Limited interaction data available

Monitoring

Before Use

• Baseline immune function assessment
• Identify specific infection/condition
• Rule out contraindicated conditions
• Establish treatment goals

During Use

• Monitor infection/wound progress
• Watch for adverse reactions
• Track inflammatory markers if relevant
• Adjust based on response

Signs of Concern

• Excessive inflammation
• Allergic reactions
• Worsening of autoimmune symptoms
• Skin rashes or reactions

Regulatory

Current Status

| Region | Status | |--------|--------| | United States | Not FDA approved; investigational | | Clinical Trials | Multiple ongoing for various indications | | WADA | Not prohibited | | Availability | Research chemical suppliers |

Legal Considerations

• Available as research chemical
• Not approved for therapeutic use
• Active clinical development by some companies
• Quality and purity variable

Clinical Development

LL-37 and derivatives are in development for:

• Chronic wound healing
• Diabetic foot ulcers
• Resistant bacterial infections
• Respiratory infections

References