Augmentation of the Lipopolysaccharide-Neutralizing Activities of Human Cathelicidin CAP18/LL-37-Derived Antimicrobial Peptides by Replacement with Hydrophobic and Cationic Amino Acid Residues

Abstract

Mammalian myeloid and epithelial cells express various peptide antibiotics (such as defensins with three K residues, the cationicity of the peptide (18-mer LLKKK) was enhanced. Among peptide derivatives, 18-mer LLKKK displayed the most powerful LPS-neutralizing activity: it was most potent at binding to LPS, inhibiting the interaction between LPS and LPS-binding protein, and attaching to the CD14 molecule, thereby suppressing the binding of LPS to CD14؉ cells and attenuating production of tumor necrosis factor alpha (TNF-␣) by these cells. Furthermore, in the murine endotoxin shock model, 18-mer LLKKK most effectively suppressed LPS-induced TNF-␣ production and protected mice from lethal endotoxin shock. Together, these observations indicate that the LPS-neutralizing activities of the amphipathic human CAP18/LL-37-derived 18-mer peptide can be augmented by modifying its hydrophobicity and cationicity, and that 18-mer LLKKK is the most potent of the peptide derivatives, with therapeutic potential for gram-negative bacterial endotoxin shock.

Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections

“…However, LL-37 has a broader spectrum concerning the antimicrobial activity and is moreover able to induce neovascularization 15 and to demonstrate binding of bacterial endotoxin (LPS, minimal active concentration: 12.5 mg/ml) 14 or chemotactic activity for neutrophils, monocytes 33 and mast cells (effective concentration 1-10 mM). 32,34 Finally, regarding the actual resistance problem of classic antibiotics and its rapid progress, it must be mentioned that there is only a very low tendency of developing resistance to HDP. 35,36 Possible systemic side effects after systemic or local applications of LL-37 still remain a field for further investigations.…”

Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application

“…Several studies showed that the C-terminal domain of hCAP18 could neutralize various activities of LPS [20,24,34] and LTA [34]. Nagaoka et al [24] identified an 18-mer peptide derived from hCAP18/LL-37, which is also included in our 22-mer peptide. By modifying hydrophobicity and cationicity of this peptide they could augment LPS neutralizing activities of this peptide.…”

“…The peptide solutions were diluted 1:100 with acetonitrile/ water/TFA 50/50/0.2 (v/v/v) and 1 ml of each solution was mixed with 1 ml of a 10 mg/ml solution of a-cyano-4-hydroxycinnamic acid (4-ACH) in acetonitrile/water/TFA 50/50/0.2 (v/v/v) containing a mass reference peptide (VNTPEHVV-PYGLGSPSRS, bovine big-endothelin (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), MH av + = 1897.10).…”

Innate defences against methicillin‐resistant Staphylococcus aureus (MRSA) infection

“…LL37 has broad spectrum activity against Gram-positive and Gramnegative bacteria including antibiotic-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and fungi [74,90,91,97,98]. In addition to bactericidal activity, LL37 is able to bind to LPS and neutralize its endotoxin activity [89,99,100], and acts as a chemotactic factor for neutrophils, monocytes, T cells, and mast cells [90,101,102].…”