Skip to main content

De Novo Peptide Design with C3a Receptor Agonist and Antagonist Activities: Theoretical Predictions and Experimental Validation

Author(s): Bellows-Peterson, Meghan L; Fung, Ho Ki; Floudas, Christodoulos A; Kieslich, Chris A; Zhang, Li; et al

To refer to this page use:
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 (EC50 values of 25.3 and 66.2 nM) and two others were partial agonists (IC50 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.
Publication Date: 2012
Citation: Bellows-Peterson, Meghan L., Ho Ki Fung, Christodoulos A. Floudas, Chris A. Kieslich, Li Zhang, Dimitrios Morikis, Kathryn J. Wareham, Peter N. Monk, Owen A. Hawksworth, and Trent M. Woodruff. "De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation." Journal of Medicinal Chemistry 55, no. 9 (2012): 4159-4168. doi: 10.1021/jm201609k
DOI: doi:10.1021/jm201609k
ISSN: 0022-2623
EISSN: 1520-4804
Pages: 4159 - 4168
Type of Material: Journal Article
Journal/Proceeding Title: Journal of Medicinal Chemistry
Version: Author's manuscript

Items in OAR@Princeton are protected by copyright, with all rights reserved, unless otherwise indicated.