Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, B. Stefanowskiego 4/10, 90-924 Lodz, Poland.
Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, B. Stefanowskiego 4/10, 90-924 Lodz, Poland.
Trends Mol Med. 2019 Oct;25(10):915-929. doi: 10.1016/j.molmed.2019.07.003. Epub 2019 Jul 31.
G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, because of their diversity, cell-specific expression, and druggable sites accessible at the cell surface. Preclinical and clinical studies suggest that targeting GPCRs activated by fatty acid-derived lipids may have potential to improve glucose homeostasis and reduce complications in patients with type 2 diabetes (T2D). Despite the discontinued development of fasiglifam (TAK-875), the first FFA1 agonist to reach late-stage clinical trials, lipid-sensing receptors remain a viable target, albeit with a need for further characterization of their binding mode, intracellular signaling, and toxicity. Herein, we analyze general discovery trends, various signaling pathways, as well as possible challenges following activation of GPCRs that have been validated clinically to control blood glucose levels.
G 蛋白偶联受体（GPCRs）是研究最为广泛的药物靶点，因为它们具有多样性、细胞特异性表达以及可在细胞表面接触到的可药物结合部位。临床前和临床研究表明，靶向由脂肪酸衍生脂质激活的 GPCR 可能具有改善 2 型糖尿病（T2D）患者血糖稳态和减少并发症的潜力。尽管 fasiglifam（TAK-875）的开发已经停止，这是第一个进入后期临床试验的 FFA1 激动剂，但脂质感应受体仍然是一个可行的靶点，尽管需要进一步表征其结合模式、细胞内信号转导和毒性。在此，我们分析了一般的发现趋势、各种信号通路，以及在已被临床验证可控制血糖水平的 GPCR 被激活后可能出现的挑战。
