Protein-Zucker-Erkennung Grundlagen und Medizinische Anwendung am Beispiel der Tumorlektinologie

Abstract

Protein-carbohydrate interactions are involved in multifarious physiological processes. Together with antibodies and enzymes, lectins constitute the family of carbohydrate-binding proteins. The current research activities of tumor lectinology comprise the design of custom-made carrier-immobilized carbohydrate ligands (neoglycoconjugates), their application for the detection of specific binding sites and the evaluation of potential therapeutical approaches by blocking access or by directing drug conjugates to cell surface lectins, correlation of their expression to clinical parameters such as prognosis and their biochemical characterization. Thereby, mammalian lectins are made available to serve as tools. These experimental approaches are evaluated as regards their potential for improving cancer diagnosis and therapy.

NMR-Based, Molecular Dynamics- and Random Walk Molecular Mechanics-Supported Study of Conformational Aspects of a Carbohydrate Ligand (Galβ1-2Galβ1-R) for an Animal Galectin in the Free and in the Bound State

“…X-ray structures of bacterial toxins and a mammalian galectin indicate that the torsion angles at the glycosidic linkage of a bound galactose moiety in the crystal lattices are similar to those regions of low energy positions in solution (37)(38)(39)(40). Knowledge about the actually bound conformation will be pivotal to devise high-affinity ligands especially for clinically relevant lectins to block access to them or target drugs (41)(42)(43). Even in the absence of a complete X-ray analysis for a lectin under investigation, docking studies can be performed with the help of available data on related agglutinins (44), as currently performed.…”

Signaling Pathways for Transduction of the Initial Message of the Glycocode into Cellular Responses

“…Growth factor receptor tyrosine kinases recruit and activate (+) the enzymes involved upon ligand (L) binding. As an example of the involvement of these pathways in lectinology, it is relevant to mention that PtdIns-4, 5-P 2 synthesis increases upon cell stimulation with the immunomodulatory mistletoe lectin [see Gabius et al, 1992Gabius et al, , 1995.…”

Lectin Ligands: New Insights into Their Conformations and Their Dynamic Behavior and the Discovery of Conformer Selection by Lectins

“…When musing on how to achieve advances in the design of ligand analogs, the topological information gained by NMR experiments is conducive. In addition to blocking antibodies or lectins optimized ligands as oligosaccharides or glycomimetics may eventually find applications as clinically beneficial therapeutics in antiadhesion therapy to fight viral or bacterial infections, undesired inflammation or tumor spread, as illustrated in figure 11, or as targeting device in organ/cell type-selective drug delivery [Gabius, 1988[Gabius, , 1997b[Gabius, , 1998Karlsson, 1991;Colman, 1994;Grootenhuis et al, 1994;Gabius et al, 1995Gabius et al, , 1996Simon, 1996;Zopf and Roth, 1996;Cornejo et al, 1997;Lowe and Ward, 1997;Mahal and Bertozzi, 1997;Rice, 1997;Witczak, 1997].…”