Theoretical calculations reveal that oligosaccharides are second to no other class of biochemical oligomery in terms of coding capacity. As integral part of cellular glycoconjugates they can serve as recognitive units for receptors (lectins). Having first been detected in plants, lectins are present ubiquitously. Remarkably for this field, they serve as bacterial and viral adhesins. Following a description of these branches of lectinology to illustrate history, current status and potential for medicinal chemistry, we document that lectins are involved in a wide variety of biochemical processes including intra- and intercellular glycoconjugate trafficking, initiation of signal transduction affecting e. g. growth regulation and cell adhesion in animals. It is thus justified to compare crucial carbohydrate epitopes with the postal code ensuring correct mail routing and delivery. In view of the functional relevance of lectins the design of high-affinity reagents to occupy their carbohydrate recognition domains offers the perspective for an attractive source of new drugs. Their applications can be supposed to encompass the use as cell-type-selective determinant for targeted drug delivery and as blocking devices in anti-adhesion therapy during infections and inflammatory disease. To master the task of devising custom-made glycans/glycomimetics for this purpose, the individual enthalpic and entropic contributions in the molecular rendezvous between the sugar receptor under scrutiny and its ligand in the presence of solvent molecules undergoing positional rearrangements need to be understood and rationally exploited. As remunerative means to this end, cleverly orchestrated deployment of a panel of methods is essential. Concerning the carbohydrate ligand, its topological parameters and flexibility are assessed by the combination of computer-assisted molecular-mechanics and molecular-dynamics calculations and NMR-spectroscopic measurements. In the presence of the receptor, the latter technique will provide insights into conformational aspects of the bound ligand and into spatial vicinity of the ligand to distinct side chains of amino acids establishing the binding site in solution. Also in solution, the hydrogen-bonding pattern in the complex can be mapped with monodeoxy and monofluoro derivatives of the oligosaccharide. Together with X-ray crystallographic and microcalorimetric studies the limits of a feasible affinity enhancement can be systematically probed. With galactoside-binding lectins as instructive mo del, recent progress in this area of drug design will be documented, emphasizing the general applicability of the outlined interdisciplinary approach.
Molecular mechanics, Rhizobium meliloti, lectinology, lectins as targets, computer assisted, NMR spectoscopic, crystallographic elucidation, sugar code, chemioal tailoring, phosphodiester backbone, microheterogeneity of glycan, monomer variability, N acetylneuramicinic, transgenic pollen, nitrogen enriched nutrients, non agglutinating ricin, hydrophobic molecules, phytopathogenic fungus, phosphomannose mutase, B bearing individuals, anti adhesion therapy, NMR spectrum, parenchymal host cells
NCBI PubMed ID: 10702616Publication DOI: 10.2174/0929867003375164Journal NLM ID: 9440157Publisher: Saif Zone, Sharjah, U.A.E.: Bentham Science Publishers
Institutions: Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität, Würzburg, Germany, Institut für Physiologische Chemie, Ludwig-Maximilians-Universität, Tierärztliche Fakultät, München, Germany, Instituto de Química Física ‘Rocasolano’, Consejo Superior de Investigaciones Científicas, Madrid, Spain, Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas, Madrid, Spain, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain, Zentrale Spektroskopie, Deutsches Krebsforschungszentrum, Heidelberg, Germany
Found