Exploring the brain permeation potential of natural product-inspired macrocycles

大环物质被定义为超过12个原子的环，通常比非环分子更能穿透人体细胞。当蛋白质不显示适合小分子攻击的表面时，这一点尤其重要，因为蛋白质必须结合在人类细胞内才能产生治疗效果。大脑中的药物靶点对于治疗阿尔茨海默氏症、帕金森氏症、抑郁症、慢性疼痛和许多其他神经退行性疾病或精神疾病至关重要，这构成了一个特别的挑战，因为除了穿透细胞膜之外，还必须克服血脑屏障。在这个项目中，我们将研究大环物质是否比传统的物质类别更适合于改善大脑的通透性。我们将使用FK506结合蛋白51(FKBP51)的例子来研究这一假设，FKBP51是一种有希望但在技术上具有挑战性的治疗抑郁症、肥胖症和慢性疼痛的药物靶点。为此，我们将首先制备三个系列的大环FKBP51抑制剂，它们的环大小、相对分子质量、极性等重要的分子特征都不同。然后，我们将准备类似于大环的非大环类似物，除了环闭合。此外，为了具体探索分子灵活性的作用，我们将准备类似于所有大环产生的大环的刚性衍生物，然后将测试它们的比较器与FK506结合蛋白51的结合以及它们进入人类细胞的能力。为了评估它们对大脑可及性的潜力，我们还将测试产生的大环是否比它们的对照物质更少被转运蛋白识别，转运蛋白构成血脑屏障的主要组成部分。通过使用最先进的计算机模拟，我们将研究物质的分子形式在这一过程中的作用。最后，我们将在动物研究中测试大环是否真的能比它们的对照物质更好地渗透到大脑。然后，最好的物质将被用来证明在抑郁症、肥胖症和慢性疼痛的动物模型中改善了疗效。

Macrocyclic substances, defined as rings of more than 12 atoms, are often better at penetrating human cells better than non-cyclic molecules. This is particularly important when proteins, which do not display suitable surfaces for an attack by small molecules, have to be bound within human cells for a therapeutic effect. Drug targets in the brain, which are essential for the treatment of Alzheimer's disease, Parkinson's disease, depression, chronic pain and many other neurodegenerative or psychiatric diseases, pose a particular challenge because in addition to penetrating the cell membrane, the blood-brain barrier must also be overcome. In this project, we will examine whether macrocyclic substances are better suited than conventional substance classes to improve brain permeability. We will investigate this hypothesis using the example of the FK506-binding protein 51 (FKBP51), a promising but technically challenging drug target for depression, obesity and chronic pain. To this end, we will first prepare three series of macrocyclic FKBP51 inhibitors that differ in ring size, molecular weight, polarity, and other important molecular characteristics. We will then prepare non-macrocyclic analogs that resemble the macrocycles except for ring closure. In addition, to specifically explore the role of molecular flexibility, we will prepare rigid derivatives that also resemble the macrocycles All macrocycles produced and their comparators will then be tested for binding to the FK506-binding protein 51 and for their ability to enter human cells. In order to assess their potential for brain accessibility, we will also test whether the produced macrocycles are less recognized than their comparator substances by transporter proteins, which form a major part of the blood-brain barrier. By using state-of-the-art computer simulations, we will investigate the role of the molecular form of the substances in this process. Finally, we will test in animal studies whether the macrocycles can indeed penetrate the brain better than their comparator substances. The best substances will then be used to demonstrate improved efficacy in animal models of depression, obesity and chronic pain.