新型仿磷酸酪胺酸單元用於發展針對蛋白質酪胺酸磷酸水解酶1B的化學探針之研究

Synthesis and Evaluation of Novel Phosphotyrosine Mimetic-Containing Probes Targeting Protein Tyrosine Phosphatase 1B (PTP1B)

黃智麟(Handoko)

指導教授 ： 羅禮強

國立臺灣大學/理學院/化學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.02933

摘要

蛋白質酪胺酸磷酸水解酶1B (PTP1B)是屬於蛋白質酪胺酸磷酸水解酶 (PTP) 酵素族群之一的酵素成員，其作用為催化蛋白質磷酸酪胺酸單位的去磷酸化反應。近十幾年來，此酵素已被認知具有負向調控胰島素訊息傳遞路徑的功能，也因此引發更多的研究著重在將此酵素作為第二型糖尿病和肥胖症藥物治療的標的物。然而，由於PTP1B和T細胞蛋白質酪胺酸磷酸水解梅 (TCPTP) 之間具有高度的結構和序列相似性，因此開發出針對PTP1B具有選擇性的化學探針和抑制劑是一個必然。在本論文中，我們合成了數個含仿磷酸酪胺酸單位之化學探針，也鑑定了此探針對多種PTP的效能。初步實驗數據顯示該方向之設計確實具有可行之潛力，促使我們更進一步的以分子對接計算來改善我們的模型。經過計算模擬結果，我們合成了另外四個化學探針，並希望此探針對PTP1B具有更好的選擇性。

關鍵字

PTP1B ； TCPTP ； 選擇性表定 ； 仿磷酸酪胺酸 ； 化學探針 ； 分子對接

並列摘要

Protein tyrosine phosphatase 1B (PTP1B), a member of protein tyrosine phosphatase (PTPs) enzyme family of which the primary function is to catalytically dephosphorylate phosphotyrosine residues of their respective substrates, has for a decade been known to negatively regulate the insulin signaling pathway. This led to intense research on PTP1B as a viable therapeutic target for the treatment of type 2 diabetes and obesity. However, due to high structural and sequential homology of PTP1B with T-cell protein tyrosine phosphatase (TCPTP), it is essential to find probes and inhibitors that will preferentially target PTP1B. Herein, in this thesis we described the synthesis of several phosphotyrosine mimetic-containing probes and subsequently evaluated their performance across various PTPs. Preliminary data gave encouraging results with preferential labelling towards PTP1B, prompting us to further refine our models with the assistance of computational molecular docking software. Four additional probes were then synthesized in the hope that they could exhibit higher specificity towards PTP1B.

並列關鍵字

PTP1B ； TCPTP ； selective labelling ； phophotyrosine mimetics ； probe ； molecular docking

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