From temples to patios for carbohydrate recognition - expanding the scope of synthetic lectins.

一个分子与另一个分子的选择性结合是生物学中的一个基本过程，是生命运作的核心。出于两个原因，人们对模仿这种现象很感兴趣。首先，通过研究合成系统，我们可以揭示它们的自然对应物，并测试我们对基本原理的理解。其次，如果我们的系统能够接近它们的自然对应物，它们可能在生物学或医学中发挥有用的功能。这是一个具有挑战性的目标，因为蛋白质和核酸的能力非常强，很难匹配。然而，合成系统如果足够有效，可能具有关键优势。它们可能比生物分子更稳定，并且可以以高纯度重复获得。它们可能比生物分子小，因此更容易研究和分析。它们也可以通过完全的结构控制进行修改，基本上没有设计限制。碳水化合物是这类研究的重要目标。一方面，已知蛋白质（凝集素）与复杂碳水化合物结构（寡糖）的结合调节许多自然过程。模拟凝集素的分子在研究和医学上都有广泛的应用。另一方面，控制碳水化合物结合的原理还没有得到很好的理解，因此人们对开发这种现象的合成模型特别感兴趣。一个潜在的问题是，从水中结合碳水化合物本质上是困难的。从表面上看，碳水化合物与水分子簇非常相似，并且对于受体（天然或合成）来说区分两者是具有挑战性的。尽管存在这些困难，PI的小组最近成功地设计了一些令人惊讶的有效合成凝集素。这些分子在天然条件下以良好的亲和力和选择性结合碳水化合物，在某些意义上上级天然凝集素。然而，到目前为止，它们的范围是有限的;它们的寺庙建筑只与以全赤道取代模式为特征的一小部分碳水化合物兼容。虽然这包括一些重要的底物（例如葡萄糖），但许多应用是遥不可及的。本项目旨在通过研究一种新的受体结构（我们称之为天井）来拓宽合成凝集素的范围。该设计与成功的太阳穴有关，但经过修改，使其能够容纳碳水化合物中的轴向取代基。许多变体是可能的，并且该方法可能导致一系列具有互补选择性的合成凝集素。如果它们表现得像我们希望的那样好，这些分子可以用作生物学家研究碳水化合物在自然界中的作用的研究工具，作为诊断疾病的试剂，并可能在进一步开发后，作为具有全新作用模式的药物。

The selective binding of one molecule by another is a fundamental process in biology, central to the workings of life. There is great interest in mimicking this phenomenon for two reasons. Firstly, by studying synthetic systems we can throw light on their natural counterparts and test our understanding of the underlying principles. Secondly, if our systems can come close to their natural counterparts, they may serve useful functions in biology or medicine. This is a challenging goal, as proteins and nucleic acids are extraordinarily competent and difficult to match. However synthetic systems, if sufficiently effective, could have key advantages. They are likely to be more stable than biomolecules, and obtainable reproducibly in high purity. They are likely to be smaller than biomolecules, and therefore easier to study and characterise. They can also be modified with full structural control and essentially no design limitations.Carbohydrates are important targets for this type of research. On the one hand the binding of complex carbohydrate structures (oligosaccharides) by proteins (lectins) is known to regulate many natural processes. Molecules which mimic lectins could have a range of applications, both in research and medicine. On the other hand the principles which govern carbohydrate binding are not well understood, so there is special interest in developing synthetic models for the phenomenon. An underlying problem is that binding carbohydrates from water is intrinsically difficult. Superficially, carbohydrates are quite similar to clusters of water molecules, and it is challenging for a receptor (natural or synthetic) to distinguish one from other.Despite these difficulties, the PI's group have recently succeeded in designing some surprisingly effective synthetic lectins . These molecules bind carbohydrates under natural conditions with good affinities, and selectivities which in some senses are superior to natural lectins. However, to date their scope is limited; their temple architecture is only compatible with a narrow range of carbohydrates characterised by all-equatorial substitution patterns. Although this includes some important substrates (e.g. glucose), many applications lie out of reach. This project aims to broaden the scope of synthetic lectins by investigating a new receptor architecture, which we term the patio . The design is related to the successful temples but is modified so that it can accommodate axial substituents in the carbohydrate. Many variants are possible and it is likely that the approach could lead to a range of synthetic lectins with complementary selectivities. If they perform as well as we hope, these molecules could be used as research tools for biologists investigating the role of carbohydrates in nature, as agents for diagnosing diseases and possibly, after further development, as pharmaceuticals with a completely novel mode of action.