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Targeting Endoplasmic Reticulum α-Glucosidase I with a Single-Dose Iminosugar Treatment Protects against Lethal Influenza and Dengue Virus Infections.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-15 , DOI: 10.1021/acs.jmedchem.0c00067 Kelly L Warfield 1 , Dominic S Alonzi 2 , Johan C Hill 2 , Alessandro T Caputo 2 , Pietro Roversi 2, 3 , J L Kiappes 2 , Nicholas Sheets 4 , Matthew Duchars 1 , Raymond A Dwek 2 , Julia Biggins 5 , Dale Barnard 6 , Sujan Shresta 4 , Anthony M Treston 1 , Nicole Zitzmann 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-15 , DOI: 10.1021/acs.jmedchem.0c00067 Kelly L Warfield 1 , Dominic S Alonzi 2 , Johan C Hill 2 , Alessandro T Caputo 2 , Pietro Roversi 2, 3 , J L Kiappes 2 , Nicholas Sheets 4 , Matthew Duchars 1 , Raymond A Dwek 2 , Julia Biggins 5 , Dale Barnard 6 , Sujan Shresta 4 , Anthony M Treston 1 , Nicole Zitzmann 2
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Influenza and dengue viruses present a growing global threat to public health. Both viruses depend on the host endoplasmic reticulum (ER) glycoprotein folding pathway. In 2014, Sadat et al. reported two siblings with a rare genetic defect in ER α-glucosidase I (ER Glu I) who showed resistance to viral infections, identifying ER Glu I as a key antiviral target. Here, we show that a single dose of UV-4B (the hydrochloride salt form of N-(9'-methoxynonyl)-1-deoxynojirimycin; MON-DNJ) capable of inhibiting Glu I in vivo is sufficient to prevent death in mice infected with lethal viral doses, even when treatment is started as late as 48 h post infection. The first crystal structure of mammalian ER Glu I will constitute the basis for the development of potent and selective inhibitors. Targeting ER Glu I with UV-4B-derived compounds may alter treatment paradigms for acute viral disease through development of a single-dose therapeutic regime.
中文翻译：
以单剂量氨基糖治疗靶向内质网α-葡萄糖苷酶I可以防止致命的流感和登革热病毒感染。
流行性感冒和登革热病毒对全球公共卫生构成了日益严重的威胁。两种病毒都依赖于宿主内质网（ER）糖蛋白折叠途径。2014年，Sadat等人。报道了两个对ERα-葡萄糖苷酶I（ER Glu I）罕见的遗传缺陷的兄弟姐妹，他们对病毒感染表现出抵抗力，并将ER Glu I作为关键的抗病毒靶标。在这里，我们表明能够在体内抑制Glu I的单剂量UV-4B（N-（9'-甲氧基壬基）-1-脱氧野oji霉素的盐酸盐形式； MON-DNJ）足以防止受感染小鼠死亡即使在感染后48小时才开始治疗，也要使用致命的病毒剂量。哺乳动物ER Glu I的第一个晶体结构将构成开发有效和选择性抑制剂的基础。
更新日期：2020-04-24
中文翻译：
以单剂量氨基糖治疗靶向内质网α-葡萄糖苷酶I可以防止致命的流感和登革热病毒感染。
流行性感冒和登革热病毒对全球公共卫生构成了日益严重的威胁。两种病毒都依赖于宿主内质网（ER）糖蛋白折叠途径。2014年，Sadat等人。报道了两个对ERα-葡萄糖苷酶I（ER Glu I）罕见的遗传缺陷的兄弟姐妹，他们对病毒感染表现出抵抗力，并将ER Glu I作为关键的抗病毒靶标。在这里，我们表明能够在体内抑制Glu I的单剂量UV-4B（N-（9'-甲氧基壬基）-1-脱氧野oji霉素的盐酸盐形式； MON-DNJ）足以防止受感染小鼠死亡即使在感染后48小时才开始治疗，也要使用致命的病毒剂量。哺乳动物ER Glu I的第一个晶体结构将构成开发有效和选择性抑制剂的基础。
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