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標題: | L-艾杜糖醛酸型亞氨醣的合成和構型研究:針對MPS-I的潛在己醛醣酸鹽水解酶穩定劑 Synthesis and Conformation Study of Iduronic acid-typed Iminosugars: Potential α-L-Iduronidase Stabilizers Toward MPS-I |
作者: | Shih-Ying Chang 張世穎 |
指導教授: | 吳世雄(Shih-Hsiung Wu) |
關鍵字: | α-L-艾杜糖苷酸酶,粘多醣貯積症第I型,酵素穩定劑,亞氨基糖,構型, α-L-Iduronidase,Mucopolysaccharidosis type I,stabilizers,iminosugars,conformation, |
出版年 : | 2020 |
學位: | 碩士 |
摘要: | α-L-艾杜糖苷酸酶(IDUA) 水解硫酸皮膚素和硫酸乙酰肝素中的末端α-L-艾杜醣醛酸(IdoA)。 IDUA活性的缺乏會導致溶酶體中受質的過度堆積,從而導致粘多醣貯積症第I型(MPS-1)的發生。酶替代療法(ERT)是目前最為主流的治療方法之一,它是通過向患者體內注射人造酵素rh-α-IDUA來減少堆積的受質。但是,rh-α-IDUA非常不穩定並且昂貴,這會給患者帶來巨大的負擔。因此,目前迫切需要增強rh-α-IDUA穩定性的新方法。 能夠有效穩定蛋白質藥物rh-α-IDUA新方法之一就是在rh-α-IDUA中加入化學小分子,此一措施可能會使蛋白質更安定。依據此概念,我們計劃以該酵素水解過程中的受質和過渡態做為模擬設計新小分子,同時在C-1上具有掌性選擇性。這些結構的發想來自α-L-艾杜醣醛酸和rh-α-IDUA之間的共晶體結構。此外,還研究了α-L-艾杜醣醛酸型小分子的化學合成和構象研究。 在對這些分子進行了初步的生物學評估後,候選化合物(化合物10和6'-1)分別顯示了在熱位移測定中具穩定酶的能力和作為IDUA抑制劑的潛力。我們將選擇這兩種分子作為骨架,進一步建立多樣化的分子庫,並希望儘快開發出新的rh-α-IDUA穩定劑,甚至藥理伴侶小分子。 α-L-Iduronidase (IDUA) catalyzes the hydrolysis of the terminal α-L-Iduronic acid (IdoA) residue in glycosaminoglycans (GAGs), such as dermatan sulfate and heparan sulfate. Loss of IDUA activity results in abnormal accumulation of GAGs in lysosomes, leading to Mucopolysaccharidosis type I (MPS-I). Enzyme replacement therapy (ERT) is the most common treatment currently, reducing accumulated substrates by injecting recombinant human α-IDUA (rh-α-IDUA) into the patient. But it is difficult to burden for patients that rh-α-IDUA is highly unstable and expensive. Accordingly, new methods to enhance the stability of rh-α-IDUA are urgently needed. One of the new approaches to suppress the instability of the current protein drug, rh-α-IDUA, is to treat a desired small molecule with rh-α-IDUA, which might lead the protein more durable. Herein, we plan to design new small molecules as substrate and transition-state mimics with the specific C-1 chirality. These structures are inspired by current enzyme substrates and the co-crystal structure between α-L-Iduronic acid and human α-IDUA (hIDUA). Besides, the chemical synthesis and conformation studies toward α-L-Iduronic acid typed analogues are also investigated. After the preliminary biological evaluation of these molecules against rh-α-IDUA, the candidate compounds, 10 and 6’’-1, showed the capability of the enzyme stabilization in thermal shift assay and the ability as an inhibitor toward IDUA respectively. We will choose these two molecules as the scaffolds to further establish the diversified library and hopefully develop new rh-α-IDUA stabilizers and even pharmacological chaperone soon. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49165 |
DOI: | 10.6342/NTU202003144 |
全文授權: | 有償授權 |
顯示於系所單位: | 化學系 |
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