α_1-抗胰蛋白酶缺乏症與蛋白質構型變異疾病

α_1-Antitrypsin Deficiency and Conformational Diseases

張怡斌(Yi-Pin Chang) ； 張文祥(Wun-Shaing Wayne Chang) ； 朱延和(Yen-Ho Chu)

《化學》 63卷3期 (2005/09) Pp. 419-430

https://doi.org/10.6623/chem.2005035

摘要

蛋白質異常的聚合是許多疾病的成因，例如阿茲海默症、巴金森氏症與α_1-抗胰蛋白酶缺乏症，這一類型的疾病現在被規類為蛋白質構型變異疾病。α_1-抗胰蛋白酶是絲氨酸蛋白酶抑制劑的代表性家族成員，它的生理功能是作為嗜中性球彈性蛋白酶的自殺型抑制劑，經過其獨特的抑制酵素反應機制，可保護肺泡免於受到彈性蛋白酶的破壞，然而突變的α_1-抗胰蛋白酶會發生自發性聚合反應造成肝硬化，此外由於缺乏足夠的蛋白酶抑制劑來中和彈性蛋白酶，將造成肺氣腫。在了解疾病的致病原因之後，可行的治療策略即是利用胜酶來阻斷蛋白質的聚合反應。而近來我們更成功發展以組合化學技術來進行受質篩選的方法，提供了藥物設計上的重要資訊。

關鍵字

α_1-抗胰蛋白酶 ； 絲氨酸蛋白酶抑制劑 ； 蛋白質構型變異疾病 ； 組合化學 ； 胜肽

並列摘要

Abnormal protein aggregation is responsible for numerous diseases such as Alzheimer’s disease, Parkinson’s disease and α_1-antitrypsin deficiency (AATD). This category of diseases is now recognized as conformational diseases. α_1-Antitrypsin is the archetype of the serine protease inhibitor (serpin) superfamily, and its physiological role is a suicide substrate toward its cognate enzyme neutrophil elastase. Through an unique conformational transition, the snared elastase is neutralized and the alveolar matrices in lungs are protected from destruction. However, dysfunctional mutations can result in a loss of inhibitory activity or allow spontaneous and inappropriate intermolecular polymerization ofα_1-antitrypsin, ultimately leading to emphysema and cirrhosis. Insights of the mechanism of diseases offer a promising anti-protein polymerization strategy. Previous studies have shown that synthetic peptides can anneal to Zα_1-antitrypsin and block polymerization. Most recently, we have developed a combinatorial approach for the discovery of anti-protein polymerization ligands, valuable for the design of therapeutic agents.

並列關鍵字

α_1-antitrypsin ； serpin ； conformational disease ； combinatorial chemistry ； peptide