Session: General Posters:

One challenge in studying carbohydrate-protein interactions is the low binding affinity of individual carbohydrates. Biological systems overcome this through the multivalent presentation of carbohydrates as glycoconjugates on proteins, lipids or cell surfaces. Molecular scaffolds designed to present carbohydrates in a precise fashion can be used to mimic these glycoconjugates to gain insights into carbohydrate-protein interactions. Here, we describe the rational design of homo- and heteromultivalent precision glycomacromolecules as glycomimetics for studying carbohydrate-protein binding using galectin-3. Galectins are involved in a wide variety of biological processes including infection and immunity. Galectin-3, a prototype galectin, is a structurally unique galectin that contains an N-terminal domain capable of self-oligomerization in the presence of multivalent ligands. Furthermore, galectin-3 exhibits secondary binding sites neighboring the carbohydrate recognition domain that can be bound by non-glycosidic motifs, strengthening galectin-3 binding. In first studies, lactose-functionalized glycomacromolecules varying in carbohydrate spacing and valency were constructed stepwise via assembly of tailor-made building blocks using Fmoc-peptide coupling protocols on solid support to obtain monodisperse, sequence-controlled oligo(amidoamine) scaffolds. Scaffolds were subsequently functionalized with lactose-moieties. Further conjugation of the glycomacromolecule scaffolds to lipids allowed for their incorporation into liposomes and subsequent multivalent presentation for binding galectin-3. Next studies involved the synthesis of heteromultivalent glycomacromolecules combining lactose residues and sulfonated/sulfated non-glycosidic motifs to better understand the role of charged, non-glycosylated binding motifs in galectin-3 targeting. These glycomacromolecules were assessed using enzyme-linked immunosorbent assay-type and surface plasmon resonance inhibition studies to evaluate their ability to act as ligands for galectin-3. Results demonstrated significant enhancement in galectin-3 binding for liposomes bearing lactose-based homomultivalent precision glycomacromolecules and for heteromultivalent precision glycomacromolecules bearing sulfonated/sulfated non-glycosidic binding motifs.^[4] Current research is focused on presenting high-binding heteromultivalent galectin-3 ligands bearing sulfated/sulfonated moieties on liposomal systems for galectin-3 targeting.

Robert Wawrzinek

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