Supramolecular agents for the binding of challenging protein surface motifs

所有的生命都是由蛋白质和DNA等不同生物分子之间微弱和可逆的结合事件驱动的。化学家对这类体系研究的贡献通常是创造了一种合成的分子探针，它可以高效和选择性地结合到给定的生物分子上。这种探针分子最常见的用途是作为药物的前体--通过有效和选择性的结合来阻止行为不端的目标的行动的小有机分子。但化学探针实际上更多地被用来在生命科学中打开新的发现之门，而不是用作药物。通过选择性地与活细胞复杂环境中的目标生物分子结合，化学探针可以允许对该目标进行标记、着色、跟踪甚至功能调节，从而使关于生命过程的新发现成为可能。化学探针还可以形成生物分子活性的分子“试管”分析的基础，这在疾病诊断和药物开发分析的应用领域是有用的。在化学生物学的广阔领域中，几乎所有这些努力都依赖于蛋白质上存在的小的凹面结合口袋，这种结合口袋天生就很适合结合具有合适大小和形状的小分子，以补充受限的结合口袋。然而，大多数重要的生物分子基序没有凹陷的结合口袋，而且由于它们相对平坦、无特征的拓扑结构，它们的表面不会呈现脚趾保持，从而允许小有机分子与它们结合。这样的生物分子很少能够被化学方法研究或调节。我们的建议是为这些具有挑战性的蛋白质表面基序创建一组化学探针，使用大的、高度结构的、高表面积的超分子或宿主分子，这些超分子或宿主分子的定义是有自己的刚性、凹面结合口袋。这与蛋白质和化学探针之间通常遇到的结合事件的拓扑结构相反。我们将采用一系列现代高通量技术，使我们能够一次制造数百、数千、甚至数十亿个这样的宿主分子，并从众多具有所需特性的分子中分离出这些分子。这些进展将为生命科学研究开辟新的途径，并为新的分析和其他商业技术提供素材，使生物和生化研究成为可能。

All of life is driven by weak and reversible binding events between different biomolecules like proteins and DNA. The contributions of chemists to the study of such systems are often in the form of the creation of a synthetic molecular probe that can bind to a given biomolecule with high potency and selectivity. The most familiar use for such probe molecules is as the precursors to drugs—small organic molecules that block the action of a misbehaving target by potent and selective binding. But chemical probes are actually more often used to open new doors of discovery in the life sciences than they are used as drugs. By binding selectively to a targeted biomolecule within the complex environment of a living cell, chemical probes can allow that target to be labeled, coloured, tracked, or even functionally regulated, in ways that make new discoveries about life processes possible. Chemical probes can also form the basis for molecular “test tube” analysis of biomolecular activities that are useful in the applied areas of disease diagnostics and drug development assays. Almost all of these efforts in the vast area of Chemical Biology rely on the presence of small, concave binding pockets on proteins that are inherently well suited to binding small molecules that have the right size and shape to complement the confined binding pocket. The majority of important biomolecular motifs, however, don’t have concave binding pockets, and because of their relatively flat, featureless topologies their surfaces don’t present a toe-hold that allows small organic molecules to bind to them. Such biomolecules are rarely able to be studied or modulated by chemical approaches. Our proposal is to create a set of chemical probes for these challenging protein surface motifs using large, highly structured, high surface area ‘supermolecules’ or ‘host molecules’ that are defined by having their own rigid, concave binding pockets. This is a reversal of the topology normally encountered for binding events between proteins and chemical probes. We will adapt a battery of modern high-throughput techniques that allow us to make hundreds, thousands, or even billions of such host molecules at a time and to isolate those from among the multitude that have the desired properties. These advances will enable new avenues in life sciences research, and also provide fodder for new assays and other commercial technologies that enable biological and biochemical research.