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標題: | 透過高通量化合物篩選人類前列腺素還原酶-2小分子抑制劑 Identification of small-molecule human PTGR-2 inhibitor through high-throughput compound screening |
作者: | Meng-Lun Hsieh 謝孟倫 |
指導教授: | 張以承 |
關鍵字: | 前列腺素還原?2,過氧化小體增生活化受體γ,第2型糖尿病,降血糖藥物,小分子抑制劑, PTGR-2,PPARγ,type 2 diabetes,oral anti-diabetic agents,enzyme inhibitor, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 過氧化物酶體增殖物活化受體γ(PPARγ)主要表現在脂肪組織中,透過與配體結合,在全身能量代謝、葡萄糖恆定以及胰島素阻抗性中扮演重要的調節功能。由於它在脂肪及葡萄糖中重要的代謝功能,所以PPARγ被視為治療疾病的重要標的,例如:第二型糖尿病、脂肪肝等疾病。目前廣泛使用的抗糖尿病藥物,是一種稱為thiazolidinedione(TZD)藥物,此藥物是人工合成之PPARγ強力配體。然而,目前人工合成的PPARγ配體,會有水分滯留、體重增加、及骨質疏鬆的副作用。因此需要開發更有效能的藥物去調控PPARγ活化以調控脂肪及葡萄糖之代謝。現今,PPARγ天然的內生性配體仍不確定。我們團隊過去研究發現15-keto-PGE2為PPARγ內生性的配體, 吾人更盡一步發現前列腺素還原酶-2(PTGR2)是一種可將15-keto-PGE2代謝成為無活性13,14-dihydro-15- keto-PGE2的酵素。Ptgr2基因剔除鼠餵食在高脂高糖飲食之下,相較於對照組,變得更瘦、胰島素敏感性增加、葡萄糖耐受性增加,但沒有水分滯留及骨質疏鬆的副作用,證實抑制PTGR2為治療糖尿病與肥胖的重要新途徑。本研究,目的為開發PTGR2的小分子抑制劑,吾人利用理性藥物設計及高通量化合物篩選方式以篩選出PTGR2小分子抑制物,並進一步在細胞株透過驗證其抑制PTGR2酵素活性、活化PPARγ的能力、以及其細胞毒性。綜合以上分析,找尋最適合的抑制物以進行日後藥物最佳化與活體實驗。 Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of whole-body energy metabolism, glucose homeostasis, and insulin resistance mainly expressed in adipose tissue. PPARγ acts through transcriptional regulation of genes involved in glucose and energy homeostasis upon ligand binding. The widely used anti-diabetic agent thiazolidinediones (TZD) are potent synthetic PPARγ agonist. However, most PPARγ agonists are associated with significant side effects, such as water retention, increased adiposity, and osteoporosis. There is an urgent need to develop effective way to modulate PPARγ activity without unwanted side effects. Nowadays, the natural ligands for PPARγ are still not certain (mostly oxidized fatty acids). Our team previously found prostaglandin reductase-2 (PTGR2) can catalyze15-keto-PGE2 to 13,14-dihydro-15-keto-PGE2, and provided further evidence that15-keto-PGE2 is an endogenous PPARγ ligand. Our team further found that Ptgr2 knockout mice are leaner, more insulin sensitive, and more glucose tolerant than control in high-fat high-sucrose (HFHS) diet without fluid retention and osteoporosis, indicating PTGR2 inhibition is a novel therapeutic approach for treating type 2 diabetes and obesity. In this study, we sought to identify PTGR2 small-molecule inhibitor through rational drug design and high-throughput compound screening. We further validated the enzymatic inhibitory activities, the PPARγ transactivating activities, and the cytotoxicity of these hits. Based on this study, we identified potential PTGR2 inhibitors for further optimization and animal experiment. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59092 |
DOI: | 10.6342/NTU201701633 |
全文授權: | 有償授權 |
顯示於系所單位: | 基因體暨蛋白體醫學研究所 |
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