High Affinity Glycodendrimers for the Lectin LecB from Pseudomonas aeruginosa

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• 作者：Nathalie Berthet ; Baptiste Thomas ; Isabelle Bossu ; Emilie Dufour ; Emilie Gillon ; Julian Garcia ; Nicolas Spinelli ; Anne Imberty ; Pascal Dumy ; Olivier Renaudet
• 刊名：Bioconjugate Chemistry
• 出版年：2013
• 出版时间：September 18, 2013
• 年：2013
• 卷：24
• 期：9
• 页码：1598-1611
• 全文大小：835K
• 年卷期：v.24,no.9(September 18, 2013)
• ISSN：1520-4812

文摘

Following an iterative oxime ligation procedure, cyclopeptide (R) and lysine-based dendron (D) were combined in all possible arrangements and successively functionalized with 伪-fucose and 尾-fucose to provide a new series of hexadecavalent glycosylated scaffolds (i.e., scaffolds RD₁₆, RR₁₆, DR₁₆, and DD₁₆). These compounds and smaller analogs (tetra- and hexavalent scaffolds R₄ and R₆) were used to evaluate the influence of the ligand valency and architecture, and of the anomer configuration in the binding to the 伪Fuc-specific lectin LecB from Pseudomonas aeruginosa. Competitive enzyme-linked lectin assays (ELLA) revealed that only the RD₁₆ architecture displaying 伪Fuc (9A) reaches strong binding improvement (IC₅₀ of 0.6 nM) over 伪MeFuc, and increases the 伪-selectivity of LecB. Dissociation constant of 28 nM was measured by isothermal titration micorcalorimetry (ITC) for 9A, which represents the highest affinity ligand ever reported for LecB. ITC and molecular modeling suggested that the high affinity observed might be due to an aggregative chelate binding involving four sugar head groups and two lectins. Interestingly, unprecedented binding effects were observed with 尾-fucosylated conjugates, albeit being less active than the corresponding ligands of the 伪Fuc series. In particular, the more flexible lysine-based dendritic structures (15B and 18B) showed a slight inhibitory enhancement in comparison with those having cyclopeptide core.