De novo peptide design with C3a receptor agonist and antagonist activities: Theoretical predictions and experimental validation

Bellows-Peterson, Meghan L., Fung, Ho Ki, Floudas, Christodoulos A., Kieslich, Chris A., Zhang, Li, Morikis, Dimitrios, Wareham, Kathryn J., Monk, Peter N., Hawksworth, Owen A. and Woodruff, Trent M. (2012) De novo peptide design with C3a receptor agonist and antagonist activities: Theoretical predictions and experimental validation. Journal of Medicinal Chemistry, 55 9: 4159-4168. doi:10.1021/jm201609k


Author Bellows-Peterson, Meghan L.
Fung, Ho Ki
Floudas, Christodoulos A.
Kieslich, Chris A.
Zhang, Li
Morikis, Dimitrios
Wareham, Kathryn J.
Monk, Peter N.
Hawksworth, Owen A.
Woodruff, Trent M.
Title De novo peptide design with C3a receptor agonist and antagonist activities: Theoretical predictions and experimental validation
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2012-05-10
Sub-type Article (original research)
DOI 10.1021/jm201609k
Volume 55
Issue 9
Start page 4159
End page 4168
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2013
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Biomedical Sciences Publications
 
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Created: Mon, 27 Aug 2012, 12:57:20 EST by Dr Trent Woodruff on behalf of School of Biomedical Sciences