Laboratory of Organic Chemistry, Wageningen University , Dreijenplein 8, 6703 HB Wageningen, The Netherlands.
School of Pharmaceutical Science and Technology, Tianjin University , Tianjin 300072, China.
Acc Chem Res. 2016 Feb 16;49(2):274-85. doi: 10.1021/acs.accounts.5b00480. Epub 2016 Jan 13.
A series of diseases, ranging from cholera via travelers' diarrhea to hamburger disease, are caused by bacterially produced toxic proteins. In particular, a toxic protein unit is brought into the host cell upon binding to specific membrane-bound oligosaccharides on the host cell membrane. For example, the protein that causes cholera, cholera toxin (CT), has five identical, symmetrically placed binding pockets (B proteins), on top of which the toxic A protein resides. A promising strategy to counteract the devastating biological effects of this AB5 protein involves the development of inhibitors that can act as mimics of membrane-bound GM1 molecules, i.e., that can bind CT strongly and selectively. To reach this goal, two features are essential: First of all, the inhibitor should display oligosaccharides that resemble as much as possible the naturally occurring cell-surface pentasaccharide onto which CT normally binds, the so-called GM1 sugar (the oligosaccharide part of which is then labeled GM1os). Second, the inhibitor should be able to bind CT via multivalent interactions so as to bind CT as strongly as possible to allow for a real competition with the cell-membrane-bound GM1 molecules. In this Account, we present elements of the path that leads to strong CT inhibition by outlining the roles of multivalency and the development and use of GM1 mimics. First, multivalency effects were investigated using "sugar-coated" platforms, ranging from dendritic structures with up to eight oligosaccharides to platforms that mimicked the fivefold symmetry of CT itself. The latter goal was reached either via synthetic scaffolds like corannulene or calix[5]arene or via the development of a neolectin CT mimic that itself carries five GM1os groups. Second, the effect of the nature of the oligosaccharide appended to this platform was investigated via the use of oligosaccharides of increasing complexity, from galactose and lactose to the tetrasaccharide GM2os and eventually to GM1os itself. The combination of these threads gives rise to a series of inhibitors that can strongly bind CT, with IC50 values below 100 pM, and in some cases can even bind one-on-one.
一系列疾病，从霍乱、旅行者腹泻到汉堡病，都是由细菌产生的毒性蛋白引起的。特别是，当毒性蛋白结合到宿主细胞膜上特定的膜结合寡糖时，它会被带入宿主细胞。例如，引起霍乱的蛋白，霍乱毒素（CT），在其顶部有五个相同的、对称放置的结合口袋（B 蛋白），其上是毒性 A 蛋白。一种有前途的对抗这种 AB5 蛋白破坏性生物学效应的策略是开发可以作为膜结合 GM1 分子类似物的抑制剂，即可以强烈且选择性地结合 CT 的抑制剂。为了达到这个目标，有两个特征是必不可少的：首先，抑制剂应该显示出尽可能类似于 CT 通常结合的天然细胞表面五糖的寡糖，即所谓的 GM1 糖（其寡糖部分随后标记为 GM1os）。其次，抑制剂应该能够通过多价相互作用结合 CT，以便尽可能强烈地结合 CT，从而与细胞膜结合的 GM1 分子进行真正的竞争。在本综述中，我们通过概述多价性的作用以及 GM1 类似物的开发和使用，介绍了导致强烈 CT 抑制的途径的要素。首先，使用从带有多达八个寡糖的树枝状结构到模拟 CT 本身五重对称性的平台，研究了多价性的影响。后一个目标是通过使用诸如苝或杯[5]芳烃之类的合成支架，或通过开发本身携带五个 GM1os 基团的新凝集素 CT 类似物来实现。其次，通过使用越来越复杂的寡糖，从半乳糖和乳糖到四糖 GM2os，最终到 GM1os，研究了添加到该平台上的寡糖的性质的影响。这些线索的结合产生了一系列可以强烈结合 CT 的抑制剂，其 IC50 值低于 100 pM，在某些情况下甚至可以一对一结合。
