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* Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-University Frankfurt, Frankfurt, Germany;
Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tuebingen, Tuebingen, Germany;
Organic Chemistry II, University of Saarland, Saarbrücken, Germany;
Institut für Organische Chemie und Chemische Biologie/Zentrum fur Arzneimittelforschung, -Entwicklung und -Sicherheit, Johann Wolfgang Goethe-University Frankfurt, Frankfurt am Main, Germany;
¶ Pharmazentrum Frankfurt, Zentrum fur Arzneimittelforschung, -Entwicklung und -Sicherheit, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; and
|| Department of Gastroenterology, Medizinische Klinik 1, University Hospital, Frankfurt, Germany
Frankincense preparations, used in folk medicine to cure inflammatory diseases, showed anti-inflammatory effectiveness in animal models and clinical trials. Boswellic acids (BAs) constitute major pharmacological principles of frankincense, but their targets and the underlying molecular modes of action are still unclear. Using a BA-affinity Sepharose matrix, a 26-kDa protein was selectively precipitated from human neutrophils and identified as the lysosomal protease cathepsin G (catG) by mass spectrometry (MALDI-TOF) and by immunological analysis. In rigid automated molecular docking experiments BAs tightly bound to the active center of catG, occupying the same part of the binding site as the synthetic catG inhibitor JNJ-10311795 (2-[3-{methyl[1-(2-naphthoyl)piperidin-4-yl]amino}carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid). BAs potently suppressed the proteolytic activity of catG (IC50 of 
600 nM) in a competitive and reversible manner. Related serine proteases were significantly less sensitive against BAs (leukocyte elastase, chymotrypsin, proteinase-3) or not affected (tryptase, chymase). BAs inhibited chemoinvasion but not chemotaxis of challenged neutrophils, and they suppressed Ca2+ mobilization in human platelets induced by isolated catG or by catG released from activated neutrophils. Finally, oral administration of defined frankincense extracts significantly reduced catG activities in human blood ex vivo vs placebo. In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The financial support for this study by Pharmasan (Freiburg, Germany), Medeon (Berlin, Germany), and by the Deutsche Forschungsgemeinschaft is acknowledged.
2 Address correspondence and reprint requests to Dr. Oliver Werz, Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany. E-mail address: oliver.werz{at}uni-tuebingen.de
3 Abbreviations used in this paper: BA, β-boswellic acid; Aβ-BA, 3-O-acetyl-β- boswellic acid; AKBA, 3-O-acetyl-11-keto-β-boswellic acid; catG, cathepsin G; JNJ-10311795, 2-[3-{methyl[1-(2-naphthoyl)piperidin-4-yl]amino}carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid; HLE, human leukocyte elastase; KBA, 11-keto-β-boswellic acid; RMSD, root mean square deviation; SPR, surface plasmon resonance.
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