Abstract
The interaction of multi-LacNAc (Galβ1-4GlcNAc)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers with human galectin-1 (Gal-1) and the carbohydrate recognition domain (CRD) of human galectin-3 (Gal-3) was analyzed using NMR methods in addition to cryo-electron-microscopy and dynamic light scattering (DLS) experiments. The interaction with individual LacNAc-containing components of the polymer was studied for comparison purposes. For Gal-3 CRD, the NMR data suggest a canonical interaction of the individual small-molecule bi- and trivalent ligands with the lectin binding site and better affinity for the trivalent arrangement due to statistical effects. For the glycopolymers, the interaction was stronger, although no evidence for forming a large supramolecule was obtained. In contrast, for Gal-1, the results indicate the formation of large cross-linked supramolecules in the presence of multivalent LacNAc entities for both the individual building blocks and the polymers. Interestingly, the bivalent and trivalent presentation of LacNAc in the polymer did not produce such an increase, indicating that the multivalency provided by the polymer is sufficient for triggering an efficient binding between the glycopolymer and Gal-1. This hypothesis was further demonstrated by electron microscopy and DLS methods.
Highlights
Galectins are carbohydrate-binding lectins (15 members in humans) characterized by a carbohydrate recognition domain (CRD) responsible for affinity to terminal β-galactoside glycostructures [1]
The functionalized LacNAc derivatives used for conjugation to multivalent carriers were synthesized by chemo-enzymatic procedure from respective functionalized GlcNAc acceptors by the action of β-galactosidase from Bacillus circulans from the commercial preparation Biolacta® [25,26]
The analysis of the NMR results shows that the glycopolymers and their constituting units, which present LacNAc moieties as interaction points, are recognized by the galectins in a canonical manner through their carbohydrate-binding sites, as further demonstrated through NMRbased competition experiments
Summary
Galectins are carbohydrate-binding lectins (15 members in humans) characterized by a carbohydrate recognition domain (CRD) responsible for affinity to terminal β-galactoside glycostructures [1] This lectin family possesses a number of biological activities related to the development and progression of cancer, which is primarily associated with galectin-1 (Gal-1) and galectin-3 (Gal-3). Both Gal-1 and Gal-3 are prominent cancer-related galectins, and their expression levels have been found to be dysregulated in various cancer cells and tissues [2,3,4] They participate in cellular adhesion, invasion, angiogenesis, and metastatic processes, supporting the development and spread of tumors [5]. Their ability to induce apoptosis of T cells leads to the simultaneous suppression of the immune system during cancerogenesis [6]. Gal-1 and Gal-3 are recognized as prospective targets for therapeutical inhibition, and the search for their potent inhibitors is a widely developed line of biomedical research [7,8]
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