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

从寺庙到露台进行碳水化合物识别——扩大合成凝集素的范围。

• 批准号: EP/I028501/1
• 负责人: Anthony Davis
• 金额: $ 41.96万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FI028501%2F1
• 关键词: temples; patios; carbohydrate; recognition; expanding

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.

另一个分子对一个分子的选择性结合是生物学运作的核心生物学的基本过程。有两个原因有两个原因，对模仿这种现象引起了极大的兴趣。首先，通过研究合成系统，我们可以阐明它们的自然对应物并测​​试我们对基本原则的理解。其次，如果我们的系统可以接近其自然对应物，则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，因为蛋白质和核酸非常有能力且难以匹配。但是，如果合成系统足够有效，则可能具有关键优势。它们可能比生物分子更稳定，并且可重复获得纯度。它们可能比生物分子小，因此更易于研究和表征。它们也可以通过完整的结构控制进行修改，并且基本上没有设计局限性。碳水化合物是此类研究的重要目标。一方面，已知蛋白质（凝集素）的复杂碳水化合物结构（寡糖）的结合来调节许多自然过程。模仿凝集素的分子可以在研究和医学中具有一系列应用。另一方面，控制碳水化合物结合的原则尚不清楚，因此对于为该现象开发合成模型引起了特别的兴趣。一个潜在的问题是，从水中的结合碳水化合物本质上困难。从表面上讲，碳水化合物与水分子的簇非常相似，对于受体（天然或合成）而言，将一种与另一种区分开来是具有挑战性的。尽管存在这些困难，但PI的组最近成功地设计了一些令人惊讶的有效的合成直肠蛋白。这些分子在自然条件下结合具有良好亲和力的碳水化合物，并且在某些感觉上比天然凝集素优越的选择性。但是，迄今为止，他们的范围有限；他们的寺庙建筑仅与以全供替代模式为特征的狭窄碳水化合物兼容。尽管这包括一些重要的底物（例如葡萄糖），但许多应用都无法触及。该项目旨在通过研究一种新的受体结构来扩大合成凝集素的范围，我们将其称为露台。该设计与成功的寺庙有关，但经过修改，以便可以容纳碳水化合物中的轴向取代基。许多变体都是可能的，该方法可能会导致具有互补选择性的一系列合成凝集素。如果它们的表现和我们希望，这些分子可以用作研究碳水化合物在自然界中的作用的生物学家的研究工具，作为诊断疾病以及可能进一步发展的药物，作为具有完全新颖的作用方式的药物。

项目成果

Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.

• DOI: 10.1002/anie.201409124
• 发表时间: 2015-02-09
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Destecroix H;Renney CM;Mooibroek TJ;Carter TS;Stewart PF;Crump MP;Davis AP
• 通讯作者: Davis AP

Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water.

• DOI: 10.1002/anie.201603082
• 发表时间: 2016-08-01
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Carter, Tom S.;Mooibroek, Tiddo J.;Stewart, Patrick F. N.;Crump, Matthew P.;Galan, M. Carmen;Davis, Anthony P.
• 通讯作者: Davis, Anthony P.

Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water

用于识别水中二价碳水化合物的合成凝集素平台

• DOI: 10.1002/ange.201603082
• 发表时间: 2016
• 期刊: Angewandte Chemie
• 作者: Carter T

Observations of tetrel bonding between $sp^{3}$-carbon and THF

$sp^{3}$-carbon 和 THF 之间 tetrel 键合的观察

• DOI: 10.3204/pubdb-2021-00615
• 发表时间: 2020
• 作者: Heywood V

Synthesis and evaluation of a desymmetrised synthetic lectin: an approach to carbohydrate receptors with improved versatility.

去对称合成凝集素的合成和评估：一种具有改进多功能性的碳水化合物受体方法。

• DOI: 10.1039/c6ob00023a
• 发表时间: 2016
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Mooibroek TJ