Synthetic small-molecule RNA Glycomimetics: targets, design and medical use: scope and applications
A large variety of complex carbohydrate chains (glycans) are present in all living organisms. They are found linked to protein in glycoproteins, lipids (in glycolipids) or as free saccharides. Some of them act as specific recognition sites for carbohydrate-binding proteins (lectins). Such reading of a “glyco-code” takes important part in many biological processes, such as trafficking of cells within the body, or trafficking of glycoprotein receptors within cells, with consequent effects on inflammation, immunity and cancer.
Therefore, it has long been of medical interest to inhibit selected lectin-carbohydrate interactions. However, binding of lectins to simple saccharides is weak, and development potent drug like inhibitors has been difficult. This lecture will describe how this has been achieved in two cases, and potential uses.
In one case, the group of Magnani et all have developed small molecule inhibitors of p-selectin and E-selectin, membrane lectins acting extracellularly to direct traffick of leukocytes in inflammation and leukemia.
In another, here main case, our group has developed potent inhibitors of galectins, a family of small soluble proteins acting both extra and intracellularly, and defined by affinity for galactose. Studies in animal disease models, including KO mice, and expression levels in human tissues have suggested rate limiting roles of galectins in cancer and inflammatory disease like fibrosis. Structure based design, modifying galactose (Kd 5-10 mM) has led to small monovalent inhibitors with Kd in low nM, with and without oral availability. In a basic science project, galectin-3 has been used as a model system to study the details of protein-small ligand interaction to find what factors determine affinity, a so far unsolved problem in drug design. Some of the galectin inhibitors have been applied in animal experiments, and also entered clinical trials to treat fibrotic disease.
Lund University, Sweden
Domain 4 - UMR 3666 / U1143 - Chemical Biology of Membranes and Therapeutic Delivery