Sulfated polysaccharide, curdlan sulfate, efficiently prevents entry/fusion and restricts antibody-dependent enhancement of dengue virus infection in vitro: a possible candidate for clinical application.
Sulfated polysaccharide, curdlan sulfate, efficiently prevents entry/fusion and restricts antibody-dependent enhancement of dengue virus infection in vitro: a possible candidate for clinical application.
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DOI：
10.1371/journal.pntd.0002188
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发表时间：
2013
影响因子：
3.8
通讯作者：
Yamamoto N
中科院分区：
文献类型：
--
作者：
Ichiyama K;Gopala Reddy SB;Zhang LF;Chin WX;Muschin T;Heinig L;Suzuki Y;Nanjundappa H;Yoshinaka Y;Ryo A;Nomura N;Ooi EE;Vasudevan SG;Yoshida T;Yamamoto N
柯德兰硫酸盐是一种硫化的1-→3-β-D葡聚糖，以前被证明是一种有效的艾滋病毒进入抑制剂，在本研究中被描述为一种有效的登革病毒抑制剂。CRDS通过电子盲法对接研究，显示出与DENV包膜(E)蛋白的结合潜力。体外实验表明，CRDS能有效地抑制DENV在不同细胞中的复制。在LLC-MK2细胞中，CRDS的最低有效浓度为0.1微克/毫升，仅在10毫克/毫升以上时才有毒性。CRDS还能有效地抑制DENV-1、3和4。CRDS对DENV亚基因组复制子的复制没有抑制作用。添加时间实验表明，该化合物不仅在宿主细胞结合阶段抑制病毒感染，而且在附着后进入早期阶段(膜融合)也能抑制病毒感染。病毒经超滤装置分离后与CRDS相互作用后，病毒滴度明显降低，并且病毒吸附到涂有CRDS的烷基膜过滤器上，这表明CRDS与DENV直接结合。电子显微镜观察还表明，CRDS与病毒被膜直接相互作用，并引起病毒表面的变化。CRDS还能有效地抑制表达DC-SIGN的细胞中的DENV感染，以及对DENV-2感染的抗体依赖性增强。基于这些数据，通过灵活的受体和配体对接研究，构建了CRDS与DENV E蛋白的可能结合模型。推测CRDS的结合部位位于E蛋白二聚体结构域II和III的交界处，这是该化合物所特有的，与β-OG的结合部位明显不同。由于CRDS已经在人体上进行了试验，没有严重的副作用，因此可以考虑将其临床应用。目前还没有专门批准的用于治疗或预防登革热的抗病毒和疫苗。登革热是一种由蚊子传播的急性病毒性疾病，每年影响5000多万人。登革热病毒(DENV)进入是确定感染和使病毒复制的关键步骤。柯德兰硫酸盐(CRDS)在实验室中可抑制HIV-1的进入和繁殖。在这里，我们应用了计算结合位点识别策略，这表明CRDS可能是病毒表面E蛋白的一种可能的进入抑制物。在体外，CRDS在病毒生命周期的早期阶段有效地阻止了DENV的感染。此外，CRDS阻止抗体依赖性增强，这被认为是DENV感染患者最重要的临床观察之一。CRDS对各血清型DENV均有良好的选择性。进一步的计算对接表明，该化合物与DENV E蛋白上的一个口袋结合。由于CRDS已经在人体上进行了测试，没有严重的副作用，因此它可以很好地应用于临床。
Curdlan sulfate (CRDS), a sulfated 1→3-β-D glucan, previously shown to be a potent HIV entry inhibitor, is characterized in this study as a potent inhibitor of the Dengue virus (DENV). CRDS was identified by in silico blind docking studies to exhibit binding potential to the envelope (E) protein of the DENV. CRDS was shown to inhibit the DENV replication very efficiently in different cells in vitro. Minimal effective concentration of CRDS was as low as 0.1 µg/mL in LLC-MK2 cells, and toxicity was observed only at concentrations over 10 mg/mL. CRDS can also inhibit DENV-1, 3, and 4 efficiently. CRDS did not inhibit the replication of DENV subgenomic replicon. Time of addition experiments demonstrated that the compound not only inhibited viral infection at the host cell binding step, but also at an early post-attachment step of entry (membrane fusion). The direct binding of CRDS to DENV was suggested by an evident reduction in the viral titers after interaction of the virus with CRDS following an ultrafiltration device separation, as well as after virus adsorption to an alkyl CRDS-coated membrane filter. The electron microscopic features also showed that CRDS interacted directly with the viral envelope, and caused changes to the viral surface. CRDS also potently inhibited DENV infection in DC-SIGN expressing cells as well as the antibody-dependent enhancement of DENV-2 infection. Based on these data, a probable binding model of CRDS to DENV E protein was constructed by a flexible receptor and ligand docking study. The binding site of CRDS was predicted to be at the interface between domains II and III of E protein dimer, which is unique to this compound, and is apparently different from the β-OG binding site. Since CRDS has already been tested in humans without serious side effects, its clinical application can be considered. There is no specific approved antiviral and vaccine for treatment or prevention of dengue, an acute mosquito-transmitted viral disease that affects more than 50 million people each year. Dengue virus (DENV) entry is a critical step that establishes the infection and enables virus replication. Curdlan sulfate (CRDS) is known to inhibit the entry and propagation of HIV-1 in the laboratory. Here we applied a computational binding site identification strategy, which suggested that CRDS could be a probable entry inhibitor of the viral surface E protein. CRDS potently blocked DENV infection at an early stage of the virus lifecycle in vitro. In addition, CRDS prevented antibody dependent enhancement, which is considered to be one of the most important clinical observations in DENV-infected patients. CRDS shows a favorable selectivity index against all serotypes of DENV. Further computational docking indicates that the compound binds to a pocket on the DENV E protein. Since CRDS has already been tested in humans without serious side effects, it can be a good candidate for clinical application.
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影响因子：
3.8
作者：
Costin JM;Jenwitheesuk E;Lok SM;Hunsperger E;Conrads KA;Fontaine KA;Rees CR;Rossmann MG;Isern S;Samudrala R;Michael SF
通讯作者：
Michael SF
影响因子：
3.4
作者：
Acosta, Eliana G.;Castilla, Viviana;Damonte, Elsa B.
通讯作者：
Damonte, Elsa B.
影响因子：
14.8
作者：
Daelemans D;Pauwels R;De Clercq E;Pannecouque C
通讯作者：
Pannecouque C
DOI：
10.1016/s0035-9203(98)90969-5
发表时间：
1998-01-01
影响因子：
2.2
作者：
Evans, SG;Morrison, D;Havlik, I
通讯作者：
Havlik, I
影响因子：
82.9
作者：
Chen, YP;Maguire, T;Marks, RM
通讯作者：
Marks, RM