Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, USA.
J Med Chem. 2012 May 10;55(9):4159-68. doi: 10.1021/jm201609k. Epub 2012 Apr 20.
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.
靶向补体成分 3a 受体（C3aR）的选择性激动剂或拮抗剂被认为是治疗中风、心脏病发作、再灌注损伤和类风湿关节炎等多种疾病的可行治疗选择。我们使用我们的两阶段从头蛋白质设计框架设计了许多 C3aR 的激动剂、部分激动剂和拮抗剂。在转染 C3aR 的大鼠嗜碱性白血病细胞中使用脱颗粒测定法测试的肽中，有两种是突出的激动剂（EC（50）值为 25.3 和 66.2 nM），另外两种是部分激动剂（IC（50）值为 15.4 和 26.1 nM）。在 U937 细胞中的钙通量测定中进一步测试这些先导化合物得到了类似的结果，尽管与转染细胞相比，效力降低。当在 C3aR 抑制测定中测试时，部分激动剂也显示出完全拮抗剂活性。此外，静电势分布被证明可以潜在地区分完全激动剂和部分激动剂。
