Dataset Information

Lactose-Functionalized Carbosilane Glycodendrimers Are Highly Potent Multivalent Ligands for Galectin-9 Binding: Increased Glycan Affinity to Galectins Correlates with Aggregation Behavior.

ABSTRACT: Galectins, the glycan binding proteins, and their respective carbohydrate ligands represent a unique fundamental regulatory network modulating a plethora of biological processes. The advances in galectin-targeted therapy must be based on a deep understanding of the mechanism of ligand-protein recognition. Carbosilane dendrimers, the well-defined and finely tunable nanoscaffolds with low toxicity, are promising for multivalent carbohydrate ligand presentation to target galectin receptors. The study discloses a synthetic method for two types of lactose-functionalized carbosilane glycodendrimers (Lac-CS-DDMs). Furthermore, we report their outstanding, dendritic effect-driven affinity to tandem-type galectins, especially Gal-9. In the enzyme-linked immunosorbent assay, the affinity of the third-generation multivalent dendritic ligand bearing 32 lactose units to Gal-9 reached nanomolar values (IC₅₀ = 970 nM), being a 1400-fold more effective inhibitor than monovalent lactose for this protein. This demonstrates a game-changing impact of multivalent presentation on the inhibitory effect of a ligand as simple as lactose. Moreover, using DLS hydrodynamic diameter measurements, we correlated the increased affinity of the glycodendrimer ligands to Gal-3 and Gal-8 but especially to Gal-9 with the formation of relatively uniform and stable galectin/Lac-CS-DDM aggregates.

SUBMITTER: Mullerova M

PROVIDER: S-EPMC10646984 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lactose-Functionalized Carbosilane Glycodendrimers Are Highly Potent Multivalent Ligands for Galectin-9 Binding: Increased Glycan Affinity to Galectins Correlates with Aggregation Behavior.

Müllerová Monika M Hovorková Michaela M Závodná Táňa T Červenková Št Astná Lucie L Krupková Alena A Hamala Vojtěch V Nováková Kateřina K Topinka Jan J Bojarová Pavla P Strašák Tomáš T

Biomacromolecules 20230908 11

Galectins, the glycan binding proteins, and their respective carbohydrate ligands represent a unique fundamental regulatory network modulating a plethora of biological processes. The advances in galectin-targeted therapy must be based on a deep understanding of the mechanism of ligand-protein recognition. Carbosilane dendrimers, the well-defined and finely tunable nanoscaffolds with low toxicity, are promising for multivalent carbohydrate ligand presentation to target galectin receptors. The stu ...[more]

PMID: 37680126

Similar Datasets

Project description:Multivalent lectin-glycan interactions (MLGIs) are widespread in biology and hold the key to many therapeutic applications. However, the underlying structural and biophysical mechanisms for many MLGIs remain poorly understood, limiting our ability to design glycoconjugates to potently target specific MLGIs for therapeutic intervention. Glycosylated nanoparticles have emerged as a powerful biophysical probe for MLGIs, although how nanoparticle shape affects the MLGI molecular mechanisms remains largely unexplored. Herein, we have prepared fluorescent quantum nanorods (QRs), densely coated with α-1,2-manno-biose ligands (QR-DiMan), as multifunctional probes to investigate how scaffold geometry affects the MLGIs of a pair of closely related, tetrameric viral receptors, DC-SIGN and DC-SIGNR. We have previously shown that a DiMan-capped spherical quantum dot (QD-DiMan) gives weak cross-linking interactions with DC-SIGNR but strong simultaneous binding with DC-SIGN. Against the elongated QR-DiMan, DC-SIGN retains similarly strong simultaneous binding of all four binding sites with a single QR-DiMan (apparent K d ≈ 0.5 nM, ∼1.8 million-fold stronger than the corresponding monovalent binding), while DC-SIGNR gives both weak cross-linking and strong individual binding interactions, resulting in a larger binding affinity enhancement than that with QD-DiMan. S/TEM analysis of QR-DiMan-lectin assemblies reveals that DC-SIGNR's different binding modes arise from the different nanosurface curvatures of the QR scaffold. The glycan display at the spherical ends presents too high a steric barrier for DC-SIGNR to bind with all four binding sites; thus, it cross-links between two QR-DiMan to maximize binding multivalency, whereas the more planar character of the cylindrical center allows the glycans to bridge all binding sites in DC-SIGNR. This work thus establishes glycosylated QRs as a powerful biophysical probe for MLGIs not only to provide quantitative binding affinities and binding modes but also to demonstrate the specificity of multivalent lectins in discriminating different glycan displays in solution, dictated by the scaffold curvature.

Dataset Information

Lactose-Functionalized Carbosilane Glycodendrimers Are Highly Potent Multivalent Ligands for Galectin-9 Binding: Increased Glycan Affinity to Galectins Correlates with Aggregation Behavior.

Publications

Lactose-Functionalized Carbosilane Glycodendrimers Are Highly Potent Multivalent Ligands for Galectin-9 Binding: Increased Glycan Affinity to Galectins Correlates with Aggregation Behavior.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets