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Derivation of ligands for the complement C3a receptor from the C-terminus of C5a

Author(s): Halai, Reena; Bellows-Peterson, Meghan L; Branchett, Will; Smadbeck, James; Kieslich, Chris A; et al

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Abstract: The complement cascade is a highly sophisticated network of proteins that are well regulated and directed in response to invading pathogens or tissue injury. Complement C3a and C5a are key mediators produced by this cascade, and their dysregulation has been linked to a plethora of inflammatory and autoimmune diseases. Consequently, this has stimulated interest in the development of ligands for the receptors for these complement peptides, C3a receptor, and C5a1 (C5aR/CD88). In this study we used computational methods to design novel C5a1 receptor ligands. However, functional screening in human monocyte-derived macrophages using the xCELLigence label-free platform demonstrated altered specificity of our ligands. No agonist/antagonist activity was observed at C5a1, but we instead saw that the ligands were able to partially agonize the closely related complement receptor C3a receptor. This was verified in the presence of C3a receptor antagonist SB 290157 and in a stable cell line expressing either C5a1 or C3a receptor alone. C3a agonism has been suggested to be a potential treatment of acute neutrophil-driven traumatic pathologies, and may have great potential as a therapeutic avenue in this arena.
Publication Date: 15-Dec-2014
Citation: Halai, Reena, Meghan L. Bellows-Peterson, Will Branchett, James Smadbeck, Chris A. Kieslich, Daniel E. Croker, Matthew A. Cooper, Dimitrios Morikiis, Trent M. Woodruff, Christodoulos A. Floudas, and Peter N. Monk. "Derivation of ligands for the complement C3a receptor from the C-terminus of C5a." European Journal of Pharmacology 745 (2014): 176-181. doi: 10.1016/j.ejphar.2014.10.041
DOI: doi:10.1016/j.ejphar.2014.10.041
ISSN: 0014-2999
Pages: 176 - 181
Type of Material: Journal Article
Journal/Proceeding Title: European Journal of Pharmacology
Version: Final published version. This is an open access article.

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