Targeting the glycans of glycoproteins: a novel paradigm for antiviral therapy.
Targeting the glycans of glycoproteins: a novel paradigm for antiviral therapy.
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DOI：
10.1038/nrmicro1707
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发表时间：
2007-08
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影响因子：
--
通讯作者：
Balzarini J
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文献类型：
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作者：
Balzarini J
糖蛋白上存在的葡聚糖通常在蛋白质折叠、运输和防止降解、先天性免疫系统的有效运行以及免疫系统逃逸方面发挥关键作用，例如艾滋病毒等病原体。碳水化合物结合剂(CBAs)种类繁多，包括凝集素和合成的小分子非肽类试剂，它们与碳水化合物的分子相互作用得到了很好的描述。一些偏好甘露糖和/或N-乙酰氨基葡萄糖(GlcNAc)识别的CBAs已被证明通过阻止病毒进入过程来抑制艾滋病毒感染。它们还被证明对其他病毒有活性，如人类丙型肝炎病毒(丙型肝炎病毒)、冠状病毒和流感病毒。当HIV暴露在CBAs中时，病毒最终主要通过删除病毒包膜糖蛋白gp120上的糖链而逃脱。已有研究表明，这些变异病毒株对中和抗体具有更高的敏感性。许多其他病原体，包括丙型肝炎病毒，细菌，如结核分枝杆菌和幽门螺杆菌，寄生虫，如利什曼原虫。或真菌，如曲霉属。和假丝酵母菌，有效地利用DC上存在的C型凝集素树突状细胞特异性细胞间黏附分子3-抓取非整合素(DC-SIGN)进行传递和/或免疫抑制。这些病原体可能是主要的候选化合物，可以暴露在CBAS中，试图中断宿主的感染或传播过程。CBA治疗HIV(可能还有其他病原体)可能代表了一种具有双重作用机制的治疗方法：直接抑制病毒的捕获、传播和进入其靶细胞；以及在CBA压力下发生多糖缺失后免疫系统的重新招募，揭示了病毒包膜上先前隐藏的免疫原性表位。碳水化合物结合剂(CBAs)是一类不同的分子，可以与病毒或靶细胞上的特定糖链结构结合。Jan Balzarini描述了一种新的抗病毒机制，该机制基于CBAs与病毒包膜糖蛋白上存在的葡聚糖的特定相互作用。几种慢性病毒感染(如艾滋病毒和丙型肝炎病毒)非常普遍，对健康构成严重威胁。动物病毒对人类宿主的适应--最近流感病毒和严重急性呼吸综合征冠状病毒就是例证--也是一个持续的威胁。因此，对新的抗病毒先导化合物和新的治疗概念的需求很高。在这篇综述中，提出了一种抑制包膜病毒的原始治疗概念，该概念基于碳水化合物结合剂(CBAs)与病毒包膜糖蛋白上存在的多糖的特定相互作用。这种方法也可以扩展到其他病原体，包括寄生虫、细菌和真菌。
Glycans that are present on glycoproteins often have a pivotal role in protein folding, trafficking and protection against degradation, the efficient operation of the innate immune system and, as in the case of pathogens such as HIV, escape by the immune system. There exists a wide range of carbohydrate-binding agents (CBAs), including lectins and synthetic small-size non-peptidic agents, and their molecular interactions with carbohydrates are well described. A number of CBAs, with a preference for mannose and/or N-acetylglucosamine (GlcNAc) recognition have been shown to inhibit HIV infections by blocking the viral entry process. They have also been shown to be active against other viruses such as human hepatitis C virus (HCV), coronavirus and influenza virus. When HIV is exposed to CBAs, virus escape eventually occurs predominantly by deleting its glycans on the viral envelope glycoprotein gp120. It has been shown that such mutant virus strains have an increased sensitivity to neutralizing antibodies. Numerous other pathogens, including HCV, bacteria such as Mycobacterium tuberculosis and Helicobacter pylori, parasites such as Leishmania spp. or fungi such as Aspergillus spp. and Candida spp., efficiently use the C-type lectin dendritic-cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) present on DCs for transmission and/or immune suppression. These pathogens may represent prime candidate compounds that can be exposed to CBAs in an attempt to interrupt the infection or transmission process in the host. CBA therapy of HIV (and possibly other pathogens) may represent a therapeutic approach with a dual mechanism of action: the direct inhibition of virus capture, transmission and entry into its target cells; and the recruitment of the immune system after glycan deletions occur under CBA pressure, uncovering previously hidden immunogenic epitopes on the viral envelope. Carbohydrate-binding agents (CBAs) are a family of diverse molecules that can bind to specific glycan structures on viruses or target cells. Jan Balzarini describes a new antiviral mechanism that is based on the specific interaction of CBAs with the glycans that are present on viral-envelope glycoproteins. Several chronic viral infections (such as HIV and hepatitis C virus) are highly prevalent and are a serious health risk. The adaptation of animal viruses to the human host, as recently exemplified by influenza viruses and the severe acute respiratory syndrome coronavirus, is also a continuous threat. There is a high demand, therefore, for new antiviral lead compounds and novel therapeutic concepts. In this Review, an original therapeutic concept for suppressing enveloped viruses is presented that is based on a specific interaction of carbohydrate-binding agents (CBAs) with the glycans present on viral-envelope glycoproteins. This approach may also be extended to other pathogens, including parasites, bacteria and fungi.