設計胜肽或醣胜肽的人類凝血酶抑制劑應用於癌症治療

Abstract

凝血酶 (Thrombin) 於新式抗癌藥物的發展上是關鍵的目標。其中一個主要的原因就是和蛋白酶激活受體 (Protease Activated Receptors) 的結合當凝血酶活化蛋白酶激活受體會觸發一連串對於細胞傳遞上的訊號。例如：生長因子(growth factors)的釋放、免疫調節(immunomodulation)作用和生物上的趨化現象(chemotaxis)。 水蛭素 (Hirudin) 已被證實為凝血酶的直接性抑制劑和具有抑制人類胰臟癌細胞生長的效用.但是，水蛭素抑制凝血的現象是一項嚴重的副作用且短暫的半生期也是我們所關注的地方。因此，我們以水蛭素為模板設計出一系列的HS (HS-1到HS-26) 衍生物，由胜肽或是醣胜肽所組成的。藉由阻擋蛋白酶激活受體和凝血酶結合的現象，HS系列強調具有抗癌的作用但是減低抑制凝血的作用。 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，而且添加醣類的結構會影響其抑制癌症的效果。由動物實驗的結果顯示，醣胜肽(HS-14) 可直接抑制腫瘤生長、無抗凝血的作用，極具有發展為抗癌藥物的潛在性。

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. The thrombin inhibitor Hirudin has been found to reduce cancer growth but the anticoagulant effect is considered as side effect. We designed HS series (HS-1 to 26) peptides and glycopeptides based on the C-terminal region of hirudin which binds to thrombin exosite I, where is the site that PAR-1 bind to the thrombin. The design HS series are emphasized on anti-cancer effect which is mediated through thrombin exosite I and devoid of anticoagulant properties which is controlled by thrombin active site. We found that the ability of thrombin binding and the inhibitory effect of cancer are increased by adding glycan. The animal experiment results show that glyco-peptide (HS-14) which has the best tumor growth inhibitory effect and has no anticoagulant activity, is a potential candidate for the anti-cancer drug.