1,3-Diyne Constrained alpha-Helix Peptides: New tools for Interrogating Protein-Protein Interactions

在本研究项目中，我们将开发一种创新的实验方法，以构象约束肽折叠成α -螺旋二级结构。由此产生的分子将成为调节蛋白质相互作用的有用化学工具。蛋白质-蛋白质相互作用参与细胞功能的调节，是药物化学家们关注的目标。虽然这些分子识别事件涉及大表面积的相互作用，但发现大多数结合亲和性和特异性来自被称为相互作用“热点”的少数氨基酸残基的星群。在分子水平上，这些残基群经常被发现是特定的蛋白质二级结构，如α -螺旋、β -链/片和转构象。这些结构基序以正确的方向和间距呈现分子功能，以便与伴侣蛋白上的互补功能相互作用。虽然螺旋基序在折叠蛋白质中通常是热力学上有利的，但分离的肽通常缺乏自发采用螺旋构象的能力。因此，从活性蛋白序列中去除特定的螺旋基序需要合成修饰来连接远端残基以诱导α -螺旋构象。这些构象约束已被用于生产用于探测蛋白质-蛋白质相互作用结合表面的α -螺旋肽模拟物，并在某些情况下为药物发现提供了先导化合物。然而，在许多例子中，连接远端氨基酸残基的功能过于灵活，无法诱导螺旋结构，因此不能作为构象约束或改善肽的物理化学性质。在这个项目中，我们将通过开发基于1,3-二炔侧链到侧链桥的高度刚性构象约束来解决这一挑战，并生产功能性工具化合物来研究蛋白质-蛋白质相互作用。

In this research project, we will develop an innovative new experimental method to conformationally constrain peptides to fold into an alpha-helix secondary structure. The resulting molecules will be useful chemical tools for the regulation of protein-protein interactions.Protein-protein interactions are involved in the regulation of cellular functions and represent attractive targets to medicinal chemists. While these molecular recognition events involve interactions over large surface areas, the majority of the binding affinity and specificity has been found to originate from constellations of a few amino acid residues that are described as interaction 'hotspots'. At a molecular level, these constellations of residues are frequently found to be specific protein secondary structures such as the alpha-helix, beta-strand/sheet and turn conformations. These structural motifs present molecular functionality with the correct orientation and spacing to interact with complementing functionality on the partner protein. Although the helical motif is usually thermodynamically favoured in folded proteins, isolated peptides typically lack the ability to spontaneously adopt the helical conformation. Efforts to excise specific helical motifs from an active protein sequence have thus necessitated synthetic modifications to link distant residues to induce an alpha-helix conformation. These conformational constraints have been used to produce alpha-helical peptide mimics for probing protein-protein interaction binding surfaces and have in some instances furnished lead compounds for drug discovery. However, in many examples the functionality linking the distant amino acid residues is too flexible to induce helical structure and so does not act as a conformational constraint or improve the physicochemical properties of the peptide. In this project we will address this challenge by developing a highly rigid conformational constraint based on a 1,3-diyne side-chain to side-chain bridge and produce functional tool compounds to investigate protein-protein interactions.