Disrupting Protein-Protein Interactions with Self-Assembling Macrocycles

项目总结 长期目标是了解一类新的环状(大环)化合物的化学结构。 以及这些分子在调节蛋白质之间相互作用方面可能具有的潜力。 控制蛋白质-蛋白质相互作用是一个未被充分开发的研究领域，也是 发现新的药物线索和策略。学术实验室、生物技术公司和大型制药公司正在投资 将更多的精力投入到这些追求中。 准备戒指是一项人工合成的挑战，很少有通用的解决方案。也就是说，虽然很多人 方法已经被成功地使用，但它们可以在范围或底物特异性方面受到限制。动态 共价化学是传统合成的有力替代品，但通常结果是混合物。 产品的数量。 幸运的是，已经发现了简单的化学方法，可以通过两个步骤自发地制造分子 二聚反应生成单一的定量大环产物。这些分子的主干 提供了许多可供操纵的站点。可能影响大环选择性和亲和力的基团 朝向蛋白质靶的方向可以被结合并且环的大小可以改变。 拟议的努力集中在三个总体目标上。前两个目标是化学的。在建立了 上一阶段主题的概括性，替换对形状的影响，关键元素 药物设计，将被探索。形状影响亲和力、溶解度和重要参数，如 预测一个分子是否会跨膜。目前的研究扩展到更大的环，采用 蛋白质样形状(β-折叠)。这些工作将在PI的实验室中执行，主要使用 本科生。第三个目标是生物方面的。合作的co-i研究乳腺癌。蛋白质-蛋白质 用截断模型研究BRCA1和PALB2(乳腺癌基因产物)之间的相互作用 这是对原生系统的概括。所提出的大循环调节相互作用的能力 这些蛋白质之间的关系将被评估。

PROJECT SUMMARY The long-term objective is to understand the chemistry of a new class of ring-shaped (macrocyclic) molecules and the potential that these molecules might have in modulating interactions between proteins. Controlling protein-protein interactions is an under-explored area of research and is fertile ground for the discovery of new drug leads and strategies. Academic labs, biotech companies and big pharma are investing increasing energies into these pursuits. Preparing rings represents a synthetic challenge that rarely has a general solution. That is, while many methods have been used successfully, they can be limited in scope or substrate specificity. Dynamic covalent chemistry is a powerful alternative to traditional synthesis, but commonly, the result is a mixture of products. Fortuitously, simple chemistries have been discovered to make molecules in 2 steps that spontaneously dimerize to yield a single macrocyclic product in quantitative yield. The backbone of these molecules offers numerous sites for manipulation. Groups that could affect selectivity and affinity of the macrocycle toward a protein target can be incorporated and the size of the ring can be changed. The proposed efforts focus on three general aims. The first two aims are chemical. Having established the generality of the motif over the last period, the affect that substitution has on shape, the critical element of drug design, will be probed. Shape influences affinity, solubility and important parameters like logP which predicts whether a molecule crosses membranes. The current studies are extended to larger rings that adopt protein-like shapes (beta-sheets). These efforts will be executed in the lab of the PI using primarily undergraduates. The third aim is biological. The collaborating co-I works on breast cancer. Protein-protein interactions between BRCA1 and PALB2 (breast cancer gene products) are explored with truncated models that recapitulate the native system. The ability of the proposed macrocycles to modulate interactions between these proteins will be assessed.