High-affinity N-(2-hydroxypropyl)methacrylamide copolymers with tailored N-acetyllactosamine presentation discriminate between galectins

0521956 - ÚMCH 2021 RIV US eng J - Journal Article
Tavares, Marina Rodrigues - Bláhová, Markéta - Sedláková, Lieselotte - Elling, L. - Pelantová, Helena - Konefal, Rafal - Etrych, Tomáš - Křen, Vladimír - Bojarová, Pavla - Chytil, Petr
High-affinity N-(2-hydroxypropyl)methacrylamide copolymers with tailored N-acetyllactosamine presentation discriminate between galectins.
Biomacromolecules. Roč. 21, č. 2 (2020), s. 641-652. ISSN 1525-7797. E-ISSN 1526-4602
R&D Projects: GA MŠMT(CZ) LTC17005; GA MŠMT(CZ) LTC19038; GA ČR(CZ) GA18-01163S; GA ČR(CZ) GA17-13721S; GA ČR(CZ) GA19-01417S; GA MŠMT(CZ) LO1507
Institutional support: RVO:61389013 ; RVO:61388971
Keywords : HPMA copolymers * drug delivery systems * galectines
OECD category: Polymer science; Polymer science (MBU-M)
Impact factor: 6.988, year: 2020
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.biomac.9b01370

N-Acetyllactosamine (LacNAc, Galβ4GlcNAc) is a typical disaccharide ligand of galectins. The most abundant members of these human lectins, galectin-1 (Gal-1) and galectin-3 (Gal-3), participate in a number of pathologies including cancerogenesis and metastatic formation. In this study, we synthesized a series of fifteen N-(2-hydroxypropyl)methacrylamide (HPMA)-based glycopolymers with varying LacNAc amounts and presentations and evaluated the impact of their architecture on the binding affinity to Gal-1 and Gal-3. The controlled radical reversible addition–fragmentation chain transfer copolymerization technique afforded linear polymer precursors with comparable molecular weight (Mn ≈ 22,000 g mol–1) and narrow dispersity (D̵ ≈ 1.1). The precursors were conjugated with the functionalized LacNAc disaccharide (4–22 mol % content in glycopolymer) prepared by enzymatic synthesis under catalysis by β-galactosidase from Bacillus circulans. The structure–affinity relationship study based on the enzyme-linked immunosorbent assay revealed that the type of LacNAc presentation, individual or clustered on bi- or trivalent linkers, brings a clear discrimination (almost 300-fold) between Gal-1 and Gal-3, reaching avidity to Gal-1 in the nanomolar range. Whereas Gal-1 strongly preferred a dense presentation of individually distributed LacNAc epitopes, Gal-3 preferred a clustered LacNAc presentation. Such a strong galectin preference based just on the structure of a multivalent glycopolymer type is exceptional. The prepared nontoxic, nonimmunogenic, and biocompatible glycopolymers are prospective for therapeutic applications requiring selectivity for one particular galectin.
Permanent Link: http://hdl.handle.net/11104/0306947