Antiviral therapies targeting host ER alpha-glucosidases: current status and future directions.
Antiviral therapies targeting host ER alpha-glucosidases: current status and future directions.
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DOI：
10.1016/j.antiviral.2013.06.011
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发表时间：
2013-09
影响因子：
7.6
通讯作者：
Guo JT
中科院分区：
文献类型：
--
作者：
Chang J;Block TM;Guo JT
ER α-葡萄糖苷酶是许多包膜病毒形态发生的重要宿主因子。亚氨基糖是内质网α-葡萄糖苷酶I和II的竞争性抑制剂。亚氨基糖的广谱抗病毒作用已在体内和体外得到证实。研究人员提出了开发强效和特异性ER α-葡萄糖苷酶抑制剂的策略。以葡萄糖苷酶为靶点治疗病毒性出血热和呼吸道感染是有希望的。内质网α-葡萄糖苷酶I和II依次修剪附着在新生糖蛋白上的n -链聚糖上的三个末端葡萄糖部分。这些反应是n链聚糖加工的第一步，对许多糖蛋白的正常折叠和功能至关重要。由于大多数病毒包膜糖蛋白含有n -连接的聚糖，用1-脱氧诺吉霉素（DNJ）或castanospermine （CAST）这两种α-葡萄糖苷酶抑制剂的衍生物抑制ER α-葡萄糖苷酶，有效地破坏了广谱包膜病毒的形态发生。此外，DNJ和CAST衍生物已被证明可以防止感染几种不同黄病毒和丝状病毒的小鼠死亡，并抑制感染动物体内几种其他病毒的增殖。DNJ的n -丁基衍生物（NB-DNJ）和CAST的6 - O-bytanoyl前药（Bu-CAST）对人类免疫缺陷病毒和丙型肝炎病毒的抗病毒活性已在人体临床试验中进行了评估，并且正在进行用Bu-CAST治疗登革热患者的试验。本文综述了内质网α-葡萄糖苷酶靶向抗病毒治疗的现状，并提出了开发更有效、更特异的内质网α-葡萄糖苷酶抑制剂作为广谱、耐药的抗病毒治疗药物的策略。这些针对宿主功能的广谱抗病毒药物不依赖于耗时的病原学诊断，因此在病毒性出血热和呼吸道病毒感染的治疗中尤其有希望，这些疾病可能由许多不同的包膜RNA病毒引起，医学干预的窗口期很短。
ER α-glucosidases are essential host factors for the morphogenesis of many enveloped viruses. Imino sugars are competitive inhibitors of the ER α-glucosidases I and II. Broad-spectrum antiviral efficacies of imino sugars have been demonstrated in vitro, and in vivo. Strategies for development of potent and specific ER α-glucosidase inhibitors have been proposed. Targeting glucosidase is promising for viral hemorrhagic fever and respiratory infections. Endoplasmic reticulum (ER)-resident α-glucosidases I and II sequentially trim the three terminal glucose moieties on N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most viral envelope glycoproteins contain N-linked glycans, inhibition of ER α-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), two well-studied pharmacophores of α-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. Moreover, both DNJ and CAST derivatives have been demonstrated to prevent the death of mice infected with several distinct flaviviruses and filoviruses and suppress the multiplication of several other species of viruses in infected animals. N-Butyl derivative of DNJ (NB-DNJ) and 6 O-bytanoyl prodrug of CAST (Bu-CAST) have been evaluated in human clinical trials for their antiviral activities against human immunodeficiency virus and hepatitis C virus, and there is an ongoing trial of treating dengue patients with Bu-CAST. This article summarizes the current status of ER α-glucosidase-targeted antiviral therapy and proposes strategies for development of more efficacious and specific ER α-glucosidase inhibitors as broad-spectrum, drug resistance-refractory antiviral therapeutics. These host function-targeted, broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis, and should therefore be particularly promising in the management of viral hemorrhagic fever and respiratory tract viral infections, medical conditions that can be caused by many different enveloped RNA viruses, with a short window for medical intervention.
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DOI：
10.1038/nrmicro975
发表时间：
2004-09
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
De Clercq E
通讯作者：
De Clercq E
影响因子：
5.4
作者：
Fischer, PB;Karlsson, GB;Platt, FM
通讯作者：
Platt, FM
DOI：
10.1006/bbrc.1995.1333
发表时间：
1995-03-08
影响因子：
3.1
作者：
AHMED, SP;NASH, RJ;TYMS, AS
通讯作者：
TYMS, AS
影响因子：
5.4
作者：
Courageot, MP;Frenkiel, MP;Desprès, P
通讯作者：
Desprès, P
影响因子：
7.6
作者：
Chang, Jinhong;Schul, Wouter;Block, Timothy M.
通讯作者：
Block, Timothy M.