| OBSERVATION'S |
Most multivalency studies have involved the rational design of carbohydrate ligands. "Multivalent carbohydrate-protein interactions are at the front edge of glycobiology today," says chemistry professor René Roy of the University of Ottawa, in Ontario. "Nature uses carbohydrates in a multivalent fashion," he says, "and we're trying to mimic Mother Nature in making carbohydrate-protein interactions better." Medicinal chemists "normally design drugs that have very high affinity for a receptor--nanomolar or picomolar binding affinity," Roy says. "But in the carbohydrate field we are generally stuck with low affinities--millimolar at best. So we were never big winners in the design of drugs based on saccharides or mimics of saccharides. This is why we have collectively jumped into this concept of multivalent interaction." The affinity enhancements afforded by multivalent binding are often referred to as the cluster effect. In the cluster effect, "you get an increase in overall affinity above and beyond the multiplication factor of valency--considerably better than if you would just add up the binding affinity per ligand," Roy explains. For example, a pentavalent inhibitor may bind its target with an affinity millions of times higher than that of the corresponding monovalent ligand. Early multivalency work From a historical standpoint, Roy says, biology professor Yuan C. Lee of Johns Hopkins University was a pioneer in the study of multivalent interactions in carbohydrate chemistry. "He essentially started it all with small clusters, containing two to three sugar residues," Roy says. Roy's group also did early work on multivalency. "It started with some water-soluble polymers," Roy says. "Sialic acid is one of the carbohydrate ligands we attached to polymers, back in 1987. Then we started to make water-soluble carbohydrate polymers, which I call glycopolymers. " 'Neoglycoconjugates' is the general term for artificial or synthetic carbohydrate molecules," Roy says, "and here we're talking about multivalent neoglycoconjugates." Multivalent compounds that have been assembled by Roy's group include random-coil glycopolymers, hyperbranched polymers, glycodendrimers (sugar-containing branched spherical structures), glycodendrons (carbohydrate-derivatized half-spherical treelike compounds), and comblike dendrigrafts (compounds in which comblike branches are grafted onto a polymer backbone). With all of these compounds, the cluster effect "is clearly there," Roy says. "We have observed extremely high binding with clusters and polymers." |
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