Medicinal chemistry based on the sugar code: Fundamentals of lectinology and experimental strategies with lectins as targets

Theoretical calculations reveal that oligosaccharides are second to no othe r class of biochemical oligomery in terms of coding capacity. As integral p art of cellular glycoconjugates they can serve as recognitive units for rec eptors (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 illu strate history, current status and potential for medicinal chemistry, we do cument 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 i n animals. It is thus justified to compare crucial carbohydrate epitopes wi th the postal code ensuring correct mail routing and delivery. In view of t he 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 enco mpass the use as cell-type-selective determinant for targeted drug delivery and as blocking devices in anti-adhesion therapy during infections and inf lammatory disease. To master the task of devising custom-made glycans/glyco mimetics for this purpose, the individual enthalpic and entropic contributi ons in the molecular rendezvous between the sugar receptor under scrutiny a nd its ligand in the presence of solvent molecules undergoing positional re arrangements need to be understood and rationally exploited. As remunerativ e means to this end, cleverly orchestrated deployment of a panel of methods is essential. Concerning the carbohydrate ligand, its topological paramete rs and flexibility are assessed by the combination of computer-assisted mol ecular-mechanics and molecular-dynamics calculations and NMR-spectroscopic measurements. In the presence of the receptor, the latter technique will pr ovide insights into conformational aspects of the bound ligand and into spa tial vicinity of the ligand to distinct side chains of amino acids establis hing the binding site in solution. Also in solution, the hydrogen-bonding p attern in the complex can be mapped with monodeoxy and monofluoro derivativ es of the oligosaccharide. Together with X-ray crystallographic and microca lorimetric studies the limits of a feasible affinity enhancement can be sys tematically probed. With galactoside-binding lectins as instructive model, recent progress in this area of drug design will be documented, emphasizing the general applicability of the outlined interdisciplinary approach.