A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Bunschoten, A., Ippel, J.H., Kruijtzer, J.A.W., Feitsma, L., Haas, C.J.C., Liskamp, R.M.J. and Kemmink, J. (2011) A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds. Amino Acids, 40(2), pp. 731-740. (doi:10.1007/s00726-010-0711-3)

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Abstract

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: Bunschoten, A., Ippel, J.H., Kruijtzer, J.A.W., Feitsma, L., Haas, C.J.C., Liskamp, R.M.J., and Kemmink, J.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Amino Acids
Publisher:Springer Verlag
ISSN:0939-4451
ISSN (Online):1438-2199
Copyright Holders:Copyright © 2010 The Authors
First Published:First published in Amino Acids 40(2):731-740
Publisher Policy:Reproduced under a Creative Commons License

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