生物分子、硫醇和抗瘧藥物對於β-血紅素的生物礦化動力學之影響

The Effects of Biogenic Molecules, Thiol and Antimalarial Drugs on Biocrystallization Kinetics of β-Hematin Formation

蔡旻翰(Ming-Han Tsai)

指導教授 ： 李度

國立中央大學/工學院/化學工程與材料工程學系/碩士(2011年)

摘要

大約有40%的世界人口正處於可能遭受瘧疾感染的威脅。根據最新的統計，每年約有百餘萬的臨床病例並造成約80萬的死亡人數。瘧疾是由瘧原蟲所引起的，其中惡性瘧原蟲是造成死亡人數最多的一種瘧原蟲。雖然目前抗瘧疾藥物的治療效果良好，但是人與瘧疾的戰爭尚未結束，因為這些藥物廣泛的使用，造成了瘧疾對這些藥物逐漸產生抗藥性，所以有必要篩選及發展新的抗瘧疾藥物。目前有五種治療瘧疾的目標類型，我們著重於干擾其中hemozoin（β-hematin，其組成為ferriprotoporphyrin IX（Fe(III)PPIX））的生物結晶過程。在此論文中，我們不僅修飾了抗瘧疾藥物的篩選方法和成功的發現一種疑似可行的新藥物組合，並整合了hemozoin的生物結晶反應機制，也發現由不具催化效益的脂質（palmitic acid）和具有催化效益的脂質（1,2-dioleoyl-sn-gylcero-3-phosphocholine）混合後的脂質性質的重要性。

關鍵字

結晶 ； 瘧疾 ； 硫醇 ； 抗瘧藥物 ； 血紅素 ； 生物礦化 ； 動力學 ； 生物分子

並列摘要

About 40% of the world’s population lives in a threat from malaria infection. According to the current statistics, there were more than hundred millions of clinical cases and 800,000 deaths each year. Malaria was caused by Plasmodium parasites, which Plasmodium falciparum was one of the Plasmodium parasites that caused the most death in the world. Although the present antimalarial drugs worked well in treatments, the war against malaria was not over yet. Drug resistance began to develop due to the widely used of antimalarial drugs. Therefore, it is necessary to screen and develop new antimalarial drugs. There were five types of drug targets in malaria treatment, and we focused on interfering the biocrystallization process of hemozoin, also called β-hematin, formation (consists of ferriprotoporphyrin, Fe(III)PPIX). In this work, we not only modified the drug screening method for antimalarials and successfully developed a plausible drug combination to fight against malaria, but also mapped out the reaction mechanism for biocrystallization of hemozoin and discovered the importance of the lipid blends upon an active promoter (1,2-dioleoyl-sn-gylcero-3-phosphocholine) and an inactive promoter (palmitic acid).

並列關鍵字

biocrystallization ； hematin ； antimalarial drugs ； thiol drugs ； biogenic molecules ； kinetics ； malaria ； crystal

參考文獻

Oliveira, M. F.; Timm, B. L.; Machado, E. A.; Miranda, K.; Attias, M.; Silva, J. R.; Dansa-Petretski, M.; de Oliveira, M. A.; de Souza, W.; Pinhal, N. M.; Sousa, J. J. F.; Vugman, N. V.; Oliveira, P. L. On the Pro-oxidant Effects of Haemozoin. FEBS Lett., 2002, 512 (1-3), 139-144.

Egan, T. J. Recent Advances in Understanding the Mechanism of Hemozoin (Malaria Pigment) Formation. J. Inorg. Biochem. 2008, 102 (5-6), 1288-1299.

Ross, R. On some Peculiar Pigmented Cells Found in Two Mosquitos Fed on Malarial Blood. Br. Med. J. 1897, 2 (1929), 1786-1788.

Brown, W. H. Malarial Pigment (so-called Melanin): Its Nature and Mode of Production. J. Exp. Med. 1911, 13 (2), 290-299.

Weissbuch, I.; Leiserowitz L. Interplay Between Malaria, Crystalline Hemozoin Formation, and Antimalarial Drug Action and Design. Chem. Rev. 2008, 108 (11), 4899-4914.