針對凝血酶與蛋白酶激活受體-1間的作用設計和合成具抗癌的醣胜肽

凝血酶 (thrombin) 於新式抗癌藥物的發展上是關鍵標的。其中一個主要的原因就是與蛋白酶激活受體-1 (protease activated receptors-1) 的結合作用。當凝血酶切割活化蛋白酶激活受體會引發許多血管新生相關因子 (angiogenesis-related genes) 的上調 (up-regulated) 反應，進而促進細胞增殖 (proliferation) 的現象。另外，從多種臨床惡性樣品中也發現凝血酶活化蛋白酶激活受體-1的表現佔據高達77.3% 的比例，顯示蛋白酶激活受體-1在腫瘤生長中扮演主要作用。在我們的研究中是利用已知的凝血酶直接抑制劑-水蛭素 (hirudin) 作為模板。水蛭素已被證實具有抑制人類胰臟癌細胞生長的效用，但水蛭素抑制凝血的現象為一項嚴重的副作用也是我們所希望排除的。因此，我們設計出一系列的醣胜肽藉由阻擋蛋白酶激活受體-1和凝血酶結合的作用，強調醣胜肽具有抗癌的效果但是不影響正常凝血的作用。由我們的研究結果顯示，藉由添加醣類於胜肽鏈上可以增加其對凝血酶的結合能力，並對於與凝血酶作用時的功能和穩定性提供關鍵的作用。

關鍵字

凝血酶；癌症；蛋白酶激活受體；醣胜肽；水蛭素

並列摘要

Thrombin is a potential target for new cancer drug development because it binds to PARs (Protease Activated Receptors) to trigger a cascade of signaling events for cellular communications, such as release of growth factors, chemotaxis, and immunomodulation. Thrombin activated protease-activated receptor-1 from multiple clinical malignant samples and plays a major role in tumor growth. In our study, we used hirudin as template, which is a well-known direct thrombin inhibitor and is able to reduce cancer growth but the anticoagulant effect is considered as side effect. We have developed a new class of anticancer glycopeptides to target the exosite I of thrombin selectively without affecting the coagulation activity and found that the glycan moiety is important for the function and stability of the glycopeptides in vitro and in vivo.