title: Derivation of ligands for the complement C3a receptor from the C-terminus of C5a.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Reena
authors.initials: R
authors.lastname: Halai
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Bellows-Peterson
authors.affiliation: Department of Infection and Immunity, Sheffield University Medical School, Sheffield, UK.
authors.forename: Will
authors.initials: W
authors.lastname: Branchett
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
authors.forename: James
authors.initials: J
authors.lastname: Smadbeck
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA; Department of Bioengineering, University of California, Riverside, CA, USA.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Kieslich
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Croker
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Department of Bioengineering, University of California, Riverside, CA, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA. Electronic address: floudas@Princeton.EDU.
authors.forename: Christodoulos A
authors.initials: CA
authors.lastname: Floudas
authors.affiliation: Department of Infection and Immunity, Sheffield University Medical School, Sheffield, UK. Electronic address: p.monk@shef.ac.uk.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Monk
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D015550:Cell Degranulation; D002460:Cell Line; D015936:Complement C5a / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D015202:Protein Engineering; D051381:Rats; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D011951:Receptors, Complement / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D001559:Benzhydryl Compounds; C488033:C5AR1 protein, human; D008024:Ligands; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011994:Recombinant Proteins; C431907:SB 290157; C085567:complement C3a receptor; D015936:Complement C5a; D001120:Arginine
keywords: C3a receptor; C5a(1) receptor; Computational optimization; In silico sequence selection; Label-free screening; Peptide design