Exploring the brain permeation potential of natural product-inspired macrocycles

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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.