Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 9, Pages 4159-4168Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm201609k
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Funding
- NSF
- NIH [R01 GM52032, R24 GM069 736]
- University of California Tobacco-Related Disease Research
- Beckman Initiative for Macular Research
- US Environmental Protection Agency, EPA [R 832721-010]
- US Environmental Protection Agency's
- DoD
- Air Force Office of Scientific Research
- National Defense Science and Engineering Graduate (NDSEG) [32 CFR 168a]
- British Heart Foundation [PG/09/018/25279] Funding Source: researchfish
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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.
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