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標題: | 針對突變病毒設計與合成具有良好生體可用率之新型抗流感藥物 Design and Synthesis of Novel Anti-Influenza Agents with Increased Bioavailability to Target Mutant Viruses |
作者: | Tzu-Chen Lin 林子禎 |
指導教授: | 方俊民(Jim-Min Fang) |
關鍵字: | 流行性感冒病毒,神經胺酸?抑制劑,抗藥性,生體可用率,?轉運蛋白, influenza,neuraminidase inhibitor,drug-resistance,bioavailability,peptide transporter, |
出版年 : | 2016 |
學位: | 碩士 |
摘要: | 流行性感冒為流感病毒造成的急性呼吸道疾病,是常見的傳染性疾病。季節性流感每年都會週期性的在人類間流行,並且隨著病毒的突變也會產生偶發性的嚴重大規模流行。流感病毒脂質包膜上的血液凝集素(hemagglutinin, HA)與神經胺酸酶(neuraminidase, NA)在病毒的致病機轉中扮演了重要的角色。由於神經胺酸酶擁有相對保守的活性中心,因此針對神經胺酸酶作用的抑制劑是非常重要的流感藥物。其中口服投藥的克流感(oseltamivir phosphate, TamifluTM)是最被廣泛用於治療的神經胺酸酶抑制劑。但隨著抗流感藥物的廣泛使用,對克流感具有抗藥性的病毒突變株大量出現,因此設計對於突變的流感病毒有抑制性的抑制劑成為重要課題。
由本實驗室與中研院基因體研究中心合作開發的單磷酯零流感(tamiphosphor monoester)以及其胍基類似物(guanidino tamiphosphor monoester),不但對於突變病毒株具有抑制性,也增進零流感的生體可用率。在本篇研究中,我們合成了胺基酸修飾的單磷酯零流感化合物32–34,以期能夠被細胞膜上的肽轉運蛋白PepT1 (peptide transporter 1)辨認,並接受其為受質協助其穿膜運輸,此策略的目的為藉由分佈於小腸上皮細胞的PepT1對藥物的傳輸加強口服生體可用率。 另外為了設計新型的抗流感神經胺酸酶抑制劑,我們挑選了peramivir (RapivabTM)作為核心結構。Peramivir目前被視為治療流感的最後手段,主要提供因昏迷無法口服或吸入其他抗病毒藥物的嚴重患者的治療。但是已知一些病毒突變株對peramivir也具中等抗藥性。為了解決這個問題,我們模仿神經胺酸脢天然受質唾液酸結構中的甘油基,設計了將peramivir結構中親脂性的3-戊基以鄰二醇取代的新抑制劑67,希望達到降低抗藥性的目的。 Influenza is one of the most common infectious disease that causes seasonal epidemics and occasional global pandemics. Hemagglutinin and neuraminidase are two important membrane proteins that contribute to the pathogenicity of influenza virulence. Inhibitors against neuraminidase are particularly useful in the development of anti-influenza agents because the active sites of different neuraminidases are relatively conservative. Orally available oseltamivir phosphate (TamifluTM) is the most widely applied drug in clinical treatment among the neuraminidase inhibitors. Nevertheless, emergence of oseltamivir-resistant viruses demonstrates the need for novel inhibitor design. In our lab, we have developed a series of oseltamivir derivatives, such as the monoesters of phosphonate oseltamivir (tamiphosphor monoesters) and their guanidino analogues, to target mutant viruses with increased bioavailability. Substantial efforts are made in this work to synthesize amino acid derivatives of tamiphosphor monoesters 32–34 as a strategy to develop inhibitors with enhanced bioavailability utilizing the active transport of human peptide transporter (hPEPT1). Peramivir (RapivabTM) is another FDA approved neuraminidase inhibitor that is considered as the last medication of influenza; however, some influenza viruses with moderate drug resistance also emerge. To tackle this problem, we thus designed an analogous compound 67 by altering the 3-pentyl side chain of peramivir to a glycol moiety that resembles the glycerol chain on sialic acid, a natural NA substrate. This compound is synthesized to test its anti-influenza activity, and hopefully its efficacy in inhibition of the drug-resistant strain will increase as our expectation. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51393 |
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