LL-37

LL-37 is a 37-amino-acid peptide derived from the C-terminal end of the human cathelicidin antimicrobial peptide (hCAP18). It is the only cathelicidin found in humans and serves as a critical component of the innate immune system. LL-37 is produced by neutrophils, macrophages, and epithelial cells and is found in various body fluids including sweat, saliva, and breast milk. Its antimicrobial activity spans a remarkable range, with demonstrated effectiveness against over 38 species of bacteria, 16 fungi, and 16 viruses.

Beyond its direct antimicrobial action, LL-37 plays important roles in modulating immune responses, promoting wound healing, and influencing angiogenesis. The peptide disrupts microbial membranes through electrostatic interactions with negatively charged lipid components, forming channels that lead to cell death. It also neutralizes bacterial endotoxins such as lipopolysaccharide (LPS), reducing the inflammatory cascade associated with bacterial infections. Research has shown LL-37 to be particularly effective against biofilm-forming organisms, which are notoriously difficult to treat with conventional antibiotics.

Clinical application of LL-37 faces challenges including susceptibility to proteolytic degradation, potential cytotoxicity at high concentrations, and relatively high synthesis costs. Researchers are actively developing modified analogs and delivery systems to overcome these limitations. Despite these challenges, LL-37 remains one of the most promising antimicrobial peptides for future therapeutic development, particularly for wound care and combating antibiotic-resistant infections.

LL-37 was first identified in 1995 by Zanetti, Gennaro, and colleagues as the sole member of the cathelicidin family of antimicrobial peptides in humans. It is cleaved from the precursor protein hCAP18 (human cationic antimicrobial peptide 18) by the enzyme proteinase 3, which processes the inactive precursor into the mature, antimicrobially active peptide. The name "LL-37" refers to its 37-amino-acid length and the two leucine residues at its N-terminus.

Since its discovery, LL-37 has become one of the most studied human antimicrobial peptides, with research expanding well beyond its initial characterization as an antimicrobial agent to include wound healing, immune modulation, anti-biofilm properties, and even anti-cancer activity. Several pharmaceutical companies have pursued modified LL-37 analogs to overcome the stability challenges inherent to the native peptide, which is rapidly degraded by proteases in vivo. These efforts have included D-amino acid substitutions, cyclization strategies, and nanoparticle delivery systems aimed at improving the therapeutic window of this important innate defense molecule.