Researchers tweaked a short piece of the human immune peptide LL‑37 and found some versions can kill lung cancer cells or bacteria in lab dishes without hurting red blood cells. The changes that worked involved swapping certain building blocks and adding short motifs called IIKK or LLKKL, which helped the peptide keep its helical shape and become more selective.

Cathelicidin LL-37 belongs to the class of human defense peptides and is overexpressed in many cancers. Segments of LL-37 derived through biochemical processes have a wide range of activities. In this study, novel analogs of the 13-amino acid cathelicidin 17-29 amide segment F¹⁷ KRIV²¹ QR²³ IK²⁵ DF²⁷ LR-NH₂ were prepared and examined for their antimicrobial and hemolytic activities, as well as for their cytotoxicity on cancer bronchial epithelial cells. Selected substitutions were performed on residues R²³ and K²⁵ in the hydrophilic side, V²¹ and F²⁷ in the hydrophobic side of the interphase, and F¹⁷ that interacts with cell membranes. Specific motifs IIKK and LLKKL with anticancer and antimicrobial activities isolated from animals were also inserted into the 17-29 fragment to investigate how they affect activity. Substitution of the amino-terminal positive charge by acetylation and replacement of lysine by the aliphatic leucine in the peptide analog Ac-FKRIVQRIL²⁵ DFLR-NH₂ resulted in significant cytotoxicity against A549 cancer cells with an IC₅₀ value 3.90 μg/mL, with no cytotoxicity to human erythrocytes. The peptide Ac-FKRIVQI²³ IKK²⁶ FLR-NH₂ , which incorporates the IIKK motif and the peptides FKRIVQL²³ L²⁴ KK²⁶ L²⁷ LR-NH₂ and Ac-FKRIVQL²³ L²⁴ KK²⁶ L²⁷ LR-NH₂ , which incorporate the LLKKL motif, displayed potent antimicrobial activity against gram-negative bacteria (MIC 3-7.5 μg/mL) and substantial cytotoxicity against bronchial epithelial cancer cells, (IC₅₀ 12.9-9.8 μg/mL), with no cytotoxic activity for human erythrocytes. The helical conformation of the synthetic peptides was confirmed by circular dichroism. Our study shows that appropriate substitutions, mainly in positions of the interphase, as well as the insertion of the motifs IIKK and LLKKL in the cathelicidin 17-29 segment, may lead to the preparation of effective biological compounds.