Hu Yaogang, Cheng Ni, Wu Haifan, Kang Samuel, Ye Richard D, Cai Jianfeng
Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620 (USA).
Chembiochem. 2014 Nov 3;15(16):2420-6. doi: 10.1002/cbic.201402396. Epub 2014 Sep 15.
The tripeptide N-formyl-Met-Leu-Phe (fMLF) is a potent neutrophil chemoattractant and the reference agonist for the G protein-coupled N-formylpeptide receptor (FPR). As it plays a very important role in host defense and inflammation, there has been considerable interest in the development of fMLF analogues in the hope of identifying potential therapeutic agents. Herein we report the design, synthesis, and evaluation of AApeptides that mimic the structure and function of fMLF. The lead AApeptides induced calcium mobilization and mitogen-activated protein kinase (MAPK) signal transduction pathways in FPR-transfected rat basophilic leukemic (RBL) cells. More intriguingly, at high concentrations, certain AApeptides were more effective than fMLF in the induction of calcium mobilization. Their agonistic activity is further supported by their ability to stimulate chemotaxis and the production of superoxide in HL-60 cells. Similarly to fMLF, these AApeptides are much more selective towards FPR1 than FPR2. These results suggest that the fMLF-mimicking AApeptides might emerge as a new class of therapeutic agents that target FPRs.
三肽N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLF）是一种有效的中性粒细胞趋化剂，也是G蛋白偶联N-甲酰肽受体（FPR）的参考激动剂。由于其在宿主防御和炎症中起着非常重要的作用，人们对开发fMLF类似物以寻找潜在治疗药物产生了浓厚兴趣。在此，我们报告了模拟fMLF结构和功能的AA肽的设计、合成及评估。先导AA肽在转染FPR的大鼠嗜碱性白血病（RBL）细胞中诱导钙动员和丝裂原活化蛋白激酶（MAPK）信号转导通路。更有趣的是，在高浓度下，某些AA肽在诱导钙动员方面比fMLF更有效。它们刺激HL-60细胞趋化和产生超氧化物的能力进一步支持了其激动活性。与fMLF类似，这些AA肽对FPR1的选择性远高于FPR2。这些结果表明，模拟fMLF的AA肽可能成为一类针对FPRs的新型治疗药物。
