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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-02-0641. This Article Full Text (PDF) All Versions of this Article: 2002-02-0641v1 100/10/3570    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Molenaar, T. J M Articles by Biessen, E. A L Search for Related Content PubMed PubMed Citation Articles by Molenaar, T. J M Articles by Biessen, E. A L Social Bookmarking                   What's this? Submitted March 7, 2002 Accepted June 24, 2002 Specific inhibition of P-selectin-mediated cell adhesion by phage display-derived peptide antagonists Tom J M Molenaar, Chantal C M Appeldoorn, Sonja A M de Haas, Ingrid N Michon, Arnaud Bonnefoy, Marc F Hoylaerts, Hans Pannekoek, Theo J C van Berkel, Johan Kuiper, and Eric A L Biessen* Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, The Netherlands Amsterdam Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Medical Center, University of Amsterdam, Amsterdam, Belgium * Corresponding author; email: Biessen{at}lacdr.leidenuniv.nl. P-selectin is a leukocyte adhesion receptor expressed on activated vascular endothelium and platelets that mediates leukocyte rolling and attachment. Since P-selectin is critically involved in inflammation, we utilized phage display libraries to identify P-selectin specific peptides which might interfere with its pro-inflammatory function. Isolated phage contained a highly conserved amino acid motif. Synthetic peptides showed calcium dependent binding to P-selectin, with high selectivity over E- and L-selectin. The peptides completely antagonized adhesion of monocyte derived HL60 cells to P-selectin, and increased their rolling velocities in flow chamber experiments. Peptide truncation and alanine scanning studies indicated that an EWVDV consensus motif sufficed for effective inhibition. Intriguingly, the apparent avidity of the peptides was increased 200-fold when presented in a tetrameric form (2 µM vs. 10 nM), which is consistent with the proposed divalent interaction of P-selectin glycoprotein ligand 1 (PSGL-1) with P-selectin. As the EWVDV peptides inhibit the binding of an established glycoside ligand for P-selectin (sulfated Lewis A), it is conceivable that EWVDV interacts with or in close proximity to the actual carbohydrate recognition domain of P-selectin, without being a direct structural mimic of sialyl Lewis X. These ligands are among the most potent antagonists of P-selectin yet designed. Their high affinity, selectivity and accessible synthesis provide a promising entry to the development of new anti-inflammatory therapeutics, and might be a powerful tool to provide important information on the binding site of P-selectin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Hatakeyama, K. Sugihara, J. Nakayama, T. O. Akama, S.-M. A. Wong, H. Kawashima, J. Zhang, D. F. Smith, C. Ohyama, M. Fukuda, et al. 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Biessen Gallic Acid Antagonizes P-Selectin-Mediated Platelet-Leukocyte Interactions: Implications for the French Paradox Circulation, January 4, 2005; 111(1): 106 - 112. [Abstract] [Full Text] [PDF] W. Noppe, K. Vanhoorelbeke, I. Y. Galaev, B. Mattiasson, and H. Deckmyn A Probe for Capture and Fe3+-Induced Conformational Change of Lactoferrin Selected from Phage Displayed Peptide Libraries J Dairy Sci, October 1, 2004; 87(10): 3247 - 3255. [Abstract] [Full Text] [PDF] C. C. M. Appeldoorn, T. J. M. Molenaar, A. Bonnefoy, S. H. van Leeuwen, P. A. H. Vandervoort, M. F. Hoylaerts, T. J. C. van Berkel, and E. A. L. Biessen Rational Optimization of a Short Human P-selectin-binding Peptide Leads to Nanomolar Affinity Antagonists J. Biol. Chem., March 14, 2003; 278(12): 10201 - 10207. [Abstract] [Full Text] [PDF]

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