Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo
Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo
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DOI：
10.1016/j.antiviral.2010.11.002
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发表时间：
2011-01-01
影响因子：
7.6
通讯作者：
Block, Timothy M.
中科院分区：
文献类型：
--
作者：
Chang, Jinhong;Schul, Wouter;Block, Timothy M.
细胞α-葡糖苷酶I和II是依次修剪病毒包膜糖蛋白的N-连接寡糖中的三个末端葡萄糖的酶。该过程对于病毒糖蛋白的正确折叠和随后许多包膜病毒（包括登革病毒（DENV））的组装是必不可少的。亚氨基糖是α-葡糖苷酶和II的底物模拟物。本文报道了两种含氧烷基亚氨基糖衍生物。CM-9-78和CM-10-18在体外和治疗的动物中是α-葡糖苷酶和II的有效抑制剂，并且有效地抑制培养的人细胞的DENV感染。药代动力学研究表明，这两种化合物在大鼠中高达100 mg/kg的剂量下耐受良好，在小鼠中具有良好的药代动力学特性和生物利用度。此外，我们显示口服施用CM-9-78或CM-10-18降低小鼠中DENV的峰值病毒血症。有趣的是，虽然单独用利巴韦林治疗DENV感染的小鼠没有减少病毒血症，但利巴韦林与亚有效剂量的CM-10-18的组合疗法显示出显著增强的抗病毒活性，如病毒血症的显著减少所示。因此，我们的研究结果表明，两种广谱抗病毒药物的联合治疗可能为治疗登革病毒感染提供一种实用的方法。(C)2010爱思唯尔有限公司版权所有。
Cellular alpha-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of alpha-glucosidases land II. In this report, we show that two oxygenated alkyl imino sugar derivatives. CM-9-78 and CM-10-18, are potent inhibitors of both alpha-glucosidases land II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100 mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection. (C) 2010 Elsevier B.V. All rights reserved.