title: De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation.
abstract: Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC(50) values of 25.3 and 66.2 nM) and two others were partial agonists (IC(50) values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists.
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Bellows-Peterson
authors.forename: Ho Ki
authors.initials: HK
authors.lastname: Fung
authors.forename: Christodoulos A
authors.initials: CA
authors.lastname: Floudas
authors.forename: Chris A
authors.initials: CA
authors.lastname: Kieslich
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wareham
authors.forename: Peter N
authors.initials: PN
authors.lastname: Monk
authors.forename: Owen A
authors.initials: OA
authors.lastname: Hawksworth
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001491:Basophils; D015926:Complement C3a / Q000378:metabolism; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011951:Receptors, Complement / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055672:Static Electricity; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a