This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multivalent binding events, in which multiple ligands on one entity simultaneously interact with multiple receptors on a complementary entity, are widespread in nature. This type of interaction has been demonstrated to be mechanically and functionally distinct from its monovalent alternative and is relatively commonplace in carbohydrate-mediated biological events. The best-studied manifestations of multivalency include dramatic increased functional affinities and enhanced or even switched selectivites compared with the monovalent counterpart. Clustered ligands have also been shown to facilitate receptor di- or oligomerization, which is often a prerequisite for initiating biological responses. The prospect of exploiting the cluster effect in the design of ligands with increased functional affinities has been widely investigated and has already been successfully exploited in the synthesis of inhibitors of bacterial toxins, selectins, and of inhibitors of the binding of viruses to host cells. Studies by our laboratory have established a new manifestation of multivalency and demonstrate for the first time that bacterial sialidases, which contain a catalytic domain together with one or more carbohydrate-binding domains, are able to hydrolyze polyvalent substrates with much greater catalytic efficiency than monovalent counterparts. The striking difference in enzymatic activity displayed by these enzymes can be explained by invoking a model wherein the catalytic and lectin domains interact simultaneously with the polyvalent substrate. Inhibition studies have indicated that galactosyl residues revealed by the action of sialidases on polymeric substrates can serve as ligands for lectin domains. This observation has been exploited in the design of a novel and potent polyvalent inhibitor of the sialidase of Vibrio cholerae. This inhibitor is the first of its type in that it is not based on a sialic acid-related scaffold, and not only supports our hypothesis for the role of the lectin-binding domains in bacterial sialidases, but also demonstrates a simple way of engineering exquisite selectivity for inhibitors of modular enzymes that possess a catalytic domain together with one or more binding domains.
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