Metal Complexes as Inhibitors of Protein-Protein Interactions

尽管许多细胞过程依赖于酶促反应，但蛋白质-蛋白质相互作用占据了大量的调节途径，因此对他们的研究的兴趣激增反映了疾病状态中的关键作用。为了有效地操纵生物系统，迫切需要通过对相互作用表面的强烈和选择性识别来抑制这些相互作用的小分子。内部的“锁和钥匙”型酶-底物分子识别模型使人们对如何设计小分子抑制剂有了很好的理解。然而，目前尚不清楚在蛋白质相互作用中发生的外部“手握球”类型识别是如何用小分子复制的。蛋白质之间的相互作用涉及具有多个非共价接触的互补的大型无形表面。在这项工作中，我们将使用小型，易于制作的构建块，这些构建块可以使用模板定向合成或自组织组合在一起，以制作“蛋白质表面模拟物”；具有识别蛋白质表面并阻止其与同伴相互作用所需的分子信息的分子实体。模板导向合成和自组装是用于从较小的组件组装复杂体系结构的合成方法。它们使用组件中的信息作为构建复杂体系结构的指令集。能够做到这一点的方法对于制定了解和防治疾病的新战略至关重要。

Although many cellular processes depend upon enzymatic reactions, protein-protein interactions populate a significant number of regulatory pathways - thus an explosion of interest in their study mirrors a pivotal role in diseased states. In order to manipulate effectively biological systems, there is a pressing need for small molecules that inhibit these interactions through strong and selective recognition of the interacting surfaces. The internal 'lock and key' type enzyme-substrate molecular recognition model has led to a good understanding of how to design small molecule inhibitors. However, it is not clear how the external 'hand gripping a ball' type recognition that occurs in protein-protein interactions, can be replicated using small molecules. Protein-protein interactions involve complementary large shapeless surfaces with multiple non-covalent contacts. In this work we will use small, easy to make, building-blocks that can be brought together using either a template directed synthesis, or self-organisation, to make 'protein surface mimics'; molecular entities that posses the molecular information necessary to recognise a protein surface and block the interaction it makes with its partner. Template directed synthesis and self-assembly are methods of synthesis used to assemble complex architectures from smaller components. They use the information within the components as an instruction set for the construction of the complex architecture. Methods that can do this are essential to the development of new strategies to understand and combat disease.