Myelin associated glycoprotein (MAG) – modulation of neurite outgrowth

Another example where NMR spectroscopy plays a key role is provided by studies that are part of a joint project that involves research groups in Basel (Prof. B. Ernst), in Bremen (Prof. S. Kelm), in Hamburg (Prof. B. Meyer), and in Lübeck (Prof. Mailänder and Prof. Peters). This project focuses on the investigation of the interaction of gangliosides with a glycoprotein called myelin associated glycoprotein (MAG) that is responsible for the inhibition of neurite outgrowth upon injuries of the central nervous system (CNS). The overall goal in this project is the design of inhibitors of MAG that would eventually allow to promote neurite outgrowth and to finally heal pathological conditions such as quadriplegia. One major issue within this project is to analyze the bioactive conformation of natural ligands of MAG that may serve as templates for the design of much more potent inhibitors. To this end we have been investigating synthetic fragments of the most potent natural inhibitor of MAG, a ganglioside called GQ1bα. Our work allowed to define the bioactive conformation of the key tri- and tetrasaccharides that are now further modified to generate more drug like compounds with a high potency to inhibit MAG. An example is shown in Fig. 3 that depicts the binding of the key tetrasaccharide to MAG. In collaboration with the plastic surgeons (Prof. Mailänder) in Lübeck we have succeeded to establish neurite outgrowth assays to test the activity of potential inhibitors of MAG before they are tested in animal models. It is hoped that these efforts finally will lead to a drug that is capable of curing quadriplegic.