The Affinity of Bivalent Ligands Depends on Linker Length and Flexibility

Because HA is a protein bound to viral membrane, multivalent ligands can interact with a single trimer or by spanning neighboring trimers. Molecules that can place multiple sialic acid residues in binding sites within a trimer might be expected to

Figure 23 (A) Whitesides's sphingosine-inspired glycolipid 38. (B) Bednarski's cross-linkable liposomal constructs 39 and 40.

Figure 23 (A) Whitesides's sphingosine-inspired glycolipid 38. (B) Bednarski's cross-linkable liposomal constructs 39 and 40.

have more potent activities. Bivalent compounds designed to bind HA in this mode have been synthesized. Several compounds in which the NeuAc residues were connected by various linker units were assembled to explore the role of linker length and flexibility in HA binding [98,160].

Sabesan and coworkers investigated oligosaccharide templates to generate bivalent sialic acid presenting ligands that could occupy multiple sites within a single HA trimer [160]. Heptasaccharides 41-45 , differing only in the linkage pattern to the core galactosyl residue, were assembled using a chemoenzymatic synthesis (Fig. 24). Nuclear Overhauser effect measurements made by 1H NMR spectroscopy and Monte Carlo simulations were used to determine the distances separating the NeuAc residues within the bivalent ligands. Compounds 44 and 45 had the shortest NeuAc separation of approximately 9-10 A, and the NeuAc residues were spaced 17-19 A apart in the other analogs. The heptasaccharides were assayed for their ability to inhibit hemagglutination by influenza virus [60]. Modest increases in activity were observed; the most effective compounds in the series, the 3,6-linked (44) and 4,6-galactose-linked (45) heptasaccharides, were 10- and 8-fold more potent than monovalent analogs, respectively, when analyzed per sialic acid residue. Given the distances separating the saccharide epitopes, it is unlikely that these compounds bind to different primary sialic acid binding sites within an HA trimer. They may, however, occupy both a primary and a secondary site on HA [18,185]. The importance in multivalent binding of distance spanned and relative ligand geometries observed

0 0

Post a comment