Affiliation:
1. Molecular Pharmacy Group Department of Pharmaceutical Sciences University of Basel Klingelbergstrasse 50 4056 Basel Switzerland
2. Chemical Biology and Drug Discovery Group Department of Pharmaceutical Sciences Utrecht University Universiteitsweg 99 3584 CG Utrecht The Netherlands
3. Laboratory for Cancer Immunotherapy Department of Biomedicine University of Basel Hebelstrasse 20 4051 Basel Switzerland
4. Division of Medical Oncology University Hospital Basel Petersgraben 4 4051 Basel Switzerland
5. Biophysics Facility Department Biozentrum University of Basel Spitalstrasse 41 4056 Basel Switzerland
Abstract
AbstractCarbohydrate‐binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent‐exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec‐8, a monomeric I‐type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra‐ and hexavalent and, to an even larger extent, multivalent ligands to Siglec‐8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect.