Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
J Med Chem. 2010 Jul 8;53(13):4938-48. doi: 10.1021/jm1003705.
Human anaphylatoxin C3a, formed through cleavage of complement protein C3, is a potent effector of innate immunity via activation of its G protein coupled receptor, human C3aR. Previously reported short peptide ligands for this receptor either have low potency or lack receptor selectivity. Here we report the first small peptide agonists that are both potent and selective for human C3aR, derived from structure-activity relationships of peptides based on the C-terminus of C3a. Affinity for C3aR was examined by competitive binding with (125)I-labeled C3a to human PBMCs [corrected], agonist versus antagonist activity measured using fluorescence detection of intracellular calcium, and general selectivity monitored by C3a-induced receptor desensitization. An NMR structure for an agonist in DMSO showed a beta-turn motif that may be important for C3aR binding and activation. Derivatization produced a noncompetitive and insurmountable antagonist of C3aR. Small molecule C3a agonists and antagonists may be valuable probes of immunity and inflammatory diseases.
人过敏毒素 C3a 通过补体蛋白 C3 的裂解形成，通过其 G 蛋白偶联受体人 C3aR 的激活，是先天免疫的有效效应物。先前报道的该受体的短肽配体要么效力低，要么缺乏受体选择性。这里我们报告了第一个对人 C3aR 既有效又具有选择性的小肽激动剂，这些激动剂源自基于 C3a 羧基末端的肽的结构-活性关系。通过与（125）I 标记的 C3a 与人 PBMCs [校正]的竞争结合来检查对 C3aR 的亲和力，使用细胞内钙的荧光检测测量激动剂与拮抗剂的活性，并且通过 C3a 诱导的受体脱敏来监测一般选择性。在 DMSO 中，激动剂的 NMR 结构显示出β-转角基序，这可能对 C3aR 的结合和激活很重要。衍生化产生了 C3aR 的非竞争性和不可逾越的拮抗剂。小分子 C3a 激动剂和拮抗剂可能是免疫和炎症性疾病的有价值的探针。
