Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/97598
標題: (1) 簡潔合成神經鞘氨醇 (2) 合成對於冠狀病毒核殼蛋白N端功能區之二聚體交界面具有別構調節效果的配體 (3) 合成脂質A前驅物
(1) Concise Synthesis of Sphingosine (2) Synthesis of ligands with allosteric modulation effect of the interface of the N-terminal domain of CoV N protein dimer (3) Synthesis of precursor of Lipid A
作者: 陳逸政
Yi-Jheng Chen
關鍵字: 神經鞘氨醇
別構調節
冠狀病毒核殼蛋白
脂質A
Sphingosine
allosteric modulation
CoV N protein
Lipid A
摘要: 本篇論文的第一部分將敘述神經鞘氨醇在不同人體疾病中的重要性,由於生物研究與其價格昂貴的需求下,促使我們建立一個簡潔合成神經鞘氨醇的方法,最重要的是我們選擇了與神經鞘氨醇結構相似且成本較低的植物鞘氨醇為起始物,成功開發了兩種不同的胺基保護途徑,可由植物鞘氨醇合成而得到神經鞘氨醇。 本篇論文的第二部分將敘述冠狀病毒在全球的流行與其特性,由此選擇了具有高度序列保留性的核殼蛋白N端功能區二聚體之交界面的重要胺基酸(W43),且可作為一個有潛力的藥物結合位點,我們從市售的5-hydroxyindole合成四種配體,藉由別構調節的方式與二聚體交界面結合,之後的實驗發現其中的配體 34 相較其他配體更能深入到二聚體之交接面,也證實了配體 34 具有促進冠狀病毒核殼蛋白聚合的能力並影響其寡聚化。 本篇論文的第三部分將敘述脂質A於人體中的毒性,但具有較少的醯基鏈數量的脂質A,可以作為免疫反應的抑制劑,並且這些抑製劑在臨床試驗中可以預防因細菌感染而引起的有害影響,重點在於我們使用單一的葡萄糖胺鹽類 66 開始合成而得到雙醣,然後合成脂質A衍生物 61,提供一個未來合成目標物脂質A 49 的方法。
In the first part of this thesis will describe the importance of sphingosine in different kinds of human diseases. Because of the requirement of sphingosine for biological research and the expensive cost of sphingosine, encouraged us to establish a concise method to synthesize sphingosine. The most important point is that we chose phytosphingosine, which is similar in structure to sphingosine as the starting material and it is cost-effective. We successfully developed two synthetic methods for sphingosine from phytosphingosine by using two different amine-protective pathways. In the second part of this thesis would describe the global prevalence and characteristics of coronaviruses. Thus we chose the important amino acid (W43) at the interface of the N-terminal domain of CoV N protein dimer which is highly conserved and it could be a potential drug binding position. We synthesized four kinds of ligands from commercially available 5-hydroxyindole. These ligands can bind with the interface of the dimer by the allosteric modulation effect. We found the ligand 34 could be deeper into the interface than the other ligands by subsequent experiments. Ligands 34 was also confirmed to have the oligomerization properties of MERS-CoV N protein. In the third part of this thesis would describe the toxicity of lipid A in human body. However, lipid A with a reduced number of acyl chains can serve as an inhibitor of immune activation and these inhibitors could prevent the harmful effect causing by bacterial infections in clinical trials. The point is that we use the same glucosamine salt 66 to get the disaccharide. Then we synthesize the derivative 61 of lipid A and it could provide a method of synthesizing the target lipid A 49 in the future.
URI: http://hdl.handle.net/11455/97598
文章公開時間: 2021-08-30
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