DTriP-22抑制腸病毒71型之機制探討

Identification of a molecular target for DTriP-22, a novel Anti-enterovirus 71 Agent

陳姿君(Tzu-Chun Chen)

指導教授 ： 張晃猷 ； 施信如

國立清華大學/生命科學院/分子醫學研究所/博士(2009年)

摘要

腸病毒71型能造成幼童嚴重神經病症，發展可能之治療藥物是目前首項要務。我們研究團隊篩選出一個具有抗腸病毒潛力的新藥物-DTriP-22， 為了鑑別此化合物的病毒分子標的，我們針對對DTriP-22具有抗藥性之病毒基因進行序列分析，發現若以離胺酸置換病毒核醣核酸聚合酶上第163個氨基酸位置上之精胺酸，將可改變病毒對DTriP-22的感受性。 DTriP-22可藉由降低在病毒感染期間病毒之正股或負股核醣核酸的累積量，進而抑制病毒複製。 而在體外聚合酶活性試驗中發現，DTriP-22可抑制腸病毒71型核醣核酸聚合酶之延長多聚尿嘧啶作用的活性，而非抑制其VPg尿苷酰化作用的活性。 這些研究結果顯示了就治療腸病毒71型而言，DTriP-22是一種新的核醣核酸聚合酶抑制劑。另外，我們進一步的實驗結果也發現DTriP-22具有抑制小核醣核酸病毒科中的其他型腸病毒的能力，顯示了此化合物之抗病毒效果的廣效性。 由我們的研究成果中顯示了DTriP-22具有進一步發展為臨床使用之抗病毒藥物的潛力。

關鍵字

腸病毒71型 ； 抗病毒藥物 ； 抑制劑

並列摘要

Enterovirus 71 (EV71) has emerged as an important virulent neurotropic enterovirus in young children. DTriP-22 was found to be a novel and potent inhibitor of EV71. The molecular target of this compound was identified by analyzing DTriP-22-resistant viruses. A substitution of lysine for Arg163 in the EV71 3D polymerase rendered the virus drug-resistant. DTriP-22 exhibited the ability to inhibit viral replication by reducing viral RNA accumulation. The compound suppressed the accumulated levels of both viral positive- and negative-stranded RNA during virus infection. In vitro polymerase assay indicated that DTriP-22 inhibited the poly(U) elongation activity, but not VPg uridylylation activity, of EV71 polymerase. These findings demonstrate that a non-nucleoside analogue, DTriP-22, acts as a novel inhibitor of EV71 polymerase. DTriP-22 also exhibited a broad-spectrum of antiviral activity against other picornaviruses, which highlights its potential in the development of antiviral agents.

並列關鍵字

enterovirus 71 ； antiviral agent ； inhibitor ； DTriP-22

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