Antimicrobial Peptides of the Cathelicidin Family: Focus on LL-37 and Its Modifications

Abstract

Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is hindered by several limitations, including low proteolytic stability, cytotoxicity, and high production costs. To overcome these challenges, a wide range of design strategies have been employed to modify LL-37 and improve its therapeutic potential. LL-37-based analogs represent promising candidates for the development of next-generation antimicrobial and immunomodulatory therapies. Despite significant progress, further research is required to optimize peptide design, ensure cost-effective production, and validate long-term safety and efficacy. Advances in computational modeling, high-throughput screening, and nanotechnology will play an important role in the translation of modified cathelicidins into clinical practice. This review summarizes key strategies of chemical and structural modifications of LL-37 aimed at enhancing its functional properties. Particular attention is given to truncated and retro-analogs, which preserve or improve biological activity while exhibiting reduced toxicity and increased proteolytic resistance. Furthermore, we highlight the use of nanoscale delivery systems, which facilitate targeted delivery, prolong peptide half-life, and mitigate cytotoxic effects.

Keywords: LL-37; LL-37 analog design; antimicrobial peptides; cathelicidins; peptide engineering; peptide modification.

Figure 1

Structural organization of LL-37. (A) Schematic representation of the human cathelicidin (CAMP) gene comprising four exons. Upon transcription and translation, the gene produces the hCAP18 pre-propeptide, a protein precursor consisting of a signal peptide (orange), a cathelin-like domain (green), and the C-terminal LL-37 peptide (blue). Proteolytic cleavage by proteinase 3 (red) releases the active mature LL-37 peptide. (B) Amino acid sequence of the full-length hCAP18 pre-propeptide (black), with the LL-37 peptide (residues 134–170, highlighted in blue) obtained by proteolytic cleavage of the C-terminal region. (C) Three-dimensional structure of LL-37 in its monomeric amphipathic α-helical conformation, including N-terminal and C-terminal helical domains and a disordered C-terminal tail. All amino acid residues are indicated.

Figure 2

Amino acid sequences and structural characteristics of LL-37 and its analogs. (A) Comparative alignment of LL-37 and representative analogs, illustrating sequence modifications such as inversions, substitutions with D-amino acids or biphenylalanine (B), acetylation, and truncation. Modifications aim to optimize antimicrobial activity, reduce cytotoxicity, and enhance proteolytic resistance. Color coding: blue—canonical amino acid substitutions; red—substitution with D-amino acids; purple—substitution with biphenylalanine. (B) Helical wheel projections (heliograms) depicting the amphipathic nature of LL-37 and its analogs. The spatial distribution of hydrophobic, polar, and charged residues is visualized. Heliograms were created using Protein ORIGAMI web application. Color legend: green—hydrophobic residues; red—polar residues; blue—positively charged residues; orange—negatively charged residues; purple—residues with special properties.

Figure 3

Nanoscale LL-37 delivery systems and their therapeutic potential.