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標題: A型流感病毒NS1蛋白與宿主因子結合之功能性與抗病毒藥物標的之可行性分析(I)
Functional Analysis of Influenza a NS1 Protein-Host Factors Interactions and Evaluation of Potential as Antiviral Drug Target (I)
作者: 張功耀
關鍵字: 公共衛生學;基礎研究;nonstructural protein 1 of Influenza A (NS1A);A 形流感病毒非結構性蛋白1;干擾素;雙股核醣核酸辨識區域;核醣核酸-蛋白質交互作用;蛋白質-蛋白質交互作用;藥物先驅物;Interferons;double-stranded RNA-binding motif(dsRBM);RNA-protein interactions;protein-protein interactions;drug-lead
A 型流感病毒非結構性蛋白1 (NS1)係一病毒之毒性因子,並且已知其在宿主抗病毒機制的抑制上扮演了重要的角色。NS1 會壓制先天免疫中數個重要因子的活化,並藉此抑制宿主先天免疫系統之作用。由於經基因重組剃除了NS1 基因之重組A 型流感病毒其毒性就大為減弱,因此NS1 蛋白是一個深俱潛力的抗病毒藥物之標的分子。本計劃之長期目標即為探討NS1 蛋白作為抗病毒藥物標的可能性,而短期內則將專注在兩個主題。其一為檢查NS1 蛋白與雙股核醣核酸辨識區域(dsRBM) 間蛋白質-蛋白質交互作用對於兩個宿主蛋白,核醣核酸解旋酶A (RHA) 與Staufen 蛋白功能之影響。此外亦將以免疫共沉澱探法尋找細胞中會與NS1 結合之蛋白或核醣核酸因子來探討與NS1 蛋白間之交互作用網絡。希望藉由對這些可以與NS1 蛋白作用之宿主因子的研究與其與NS1 蛋白結合後對其功能的影響來瞭解NS1 蛋白作為病毒毒性因子的分子機制。本計劃另一個目的則為搜索NS1 蛋白N端之核醣核酸結合區與C 端之綜作用區分子表面較易被辨識之結構特徵以作為小分子藥物結合之標的。我们將藉由以生物體外選擇性篩選的方法尋找可以NS1 蛋白結合以破壞其蛋白或核醣核酸結合能力之短鍊生肽或核酸。並依此標定NS1 蛋白表面之結合熱點。結合了這兩個主題的探討,吾人將可以提供一個NS1 蛋白表面結合區之詳細資訊。

The nonstructural protein 1 (NS1) of Influenza A is a virulence factor and has been shown to playimportant roles in suppressing the antiviral defenses of the host. It has been established that NS1 caninhibit the activation of several key factors of innate immunity, and thus suppress the host innate immunesystem. Recombinant Influenza A lacking NS1A protein is shown to be highly attenuated, suggesting theNS1A protein represents a prominent antiviral drug target.The long-term objective of this proposal is to explore the potential of Influenza A NS1 protein as theantiviral target with two specific aims. The first goal is to examine the significance of specificdouble-stranded RNA-binding motif (dsRBM)-binding of NS1 on two human proteins, the Staufen andRNA helicase A (RHA). Furthermore, co-immunoprecipitation approach will be used to identify protein orRNA factors associated with NS1 in vivo to dissect the interaction network of NS1. The elucidation of thefunction and impact of NS1-binding of these factors on host antiviral and viral gene expression will thusprovide useful information for antiviral targeting and control of the rapidly spreading epidemics. Thesecond goal is to probe the surface of both the dsRNA-binding and effector domains of NS1 to look for thehot-spot suitable for ligand-binding. It will be done by screening aptamers that impair their functions inRNA-protein and protein-protein interactions respectively by in vitro selection approach. The knowledgefor such hot spots will be very informative for searching small-molecule drug-lead to target NS1. Together,this work will provide a comprehensive map of the surface of NS1 for the binding site of its cellular targetand potential blocking sites by drug-leads.
其他識別: NSC97-2321-B005-010
Appears in Collections:生物化學研究所

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