title: Boswellic acids target the human immune system-modulating antimicrobial peptide LL-37.
abstract: The antimicrobial peptide LL-37 is the sole member of the human cathelicidin family with immune system-modulating properties and roles in autoimmune disease development. Small molecules able to interact with LL-37 and to modulate its functions have not been described yet. Boswellic acids (BAs) are pentacyclic triterpene acids that are bioactive principles of frankincense extracts used as anti-inflammatory remedies. Although various anti-inflammatory modes of action have been proposed for BAs, the pharmacological profile of these compounds is still incompletely understood. Here, we describe the identification of human LL-37 as functional target of BAs. In unbiased target fishing experiments using immobilized BAs as bait and human neutrophils as target source, LL-37 was identified as binding partner assisted by MALDI-TOF mass spectrometry. Thermal stability experiments using circular dichroism spectroscopy confirm direct interaction between BAs and LL-37. Of interest, this binding of BAs resulted in an inhibition of the functionality of LL-37. Thus, the LPS-neutralizing properties of isolated LL-37 were inhibited by 3-O-acetyl-β-BA (Aβ-BA) and 3-O-acetyl-11-keto-β-BA (AKβ-BA) in a cell-free limulus amoebocyte lysate assay with EC50=0.2 and 0.8 μM, respectively. Also, LL-37 activity was inhibited by these BAs in LL-37-enriched supernatants of stimulated neutrophils or human plasma derived from stimulated human whole blood. Together, we reveal BAs as inhibitors of LL-37, which might be a relevant mechanism underlying the anti-inflammatory properties of BAs and suggests BAs as suitable chemical tools or potential agents for intervention with LL-37 and related disorders.
authors.affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany. Electronic address: arne.henkel@gmail.com.
authors.forename: Arne
authors.initials: A
authors.lastname: Henkel
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Str. 9, D-60439 Frankfurt, Germany. Electronic address: l.Tausch@yahoo.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Tausch
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland. Electronic address: max.pillong@novartis.com.
authors.forename: Max
authors.initials: M
authors.lastname: Pillong
authors.affiliation: Organic Chemistry II, University of Saarland, Campus C 4.2, D-66123 Saarbrücken, Germany. Electronic address: j.jauch@mx.uni-saarland.de.
authors.forename: Johann
authors.initials: J
authors.lastname: Jauch
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Str. 9, D-60439 Frankfurt, Germany. Electronic address: karas@pharmchem.uni-frankfurt.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Karas
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland. Electronic address: gisbert.schneider@pharma.ethz.ch.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000890:Anti-Infective Agents / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D014315:Triterpenes; C054625:boswellic acid
keywords: 11-Keto-β-boswellic acid (PubChem CID:9847548); 3-O-Acetyl-11-keto-β-boswellic acid (PubChem CID: 71,463,896); 3-O-Acetyl-β-boswellic acid (PubChem CID: 11,386,458); Boswellic acid; Cathelicidin; Cytochalasin B (PubChem CID:5311281); Frankincense; Inflammation; LL-37; LL-37 (PubChem CID: 16,198,951); Lipopolysaccharide; Lipopolysaccharide (PubChem CID: 11,970,143); N-formyl-methionyl-leucyl-phenylalanin (PubChem CID: 4364); β-Boswellic acid (PubChem CID: 168,928)