High Affinity Glycodendrimers for the Lectin LecB from Pseudomonas aeruginosa

Abstract

Following an iterative oxime ligation procedure, cyclopeptide (R) and lysine-based dendron (D) were combined in all possible arrangements and successively functionalized with α-fucose and β-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 αFuc-specific lectin LecB from Pseudomonas aeruginosa . Competitive enzyme-linked lectin assays (ELLA) revealed that only the RD16 architecture displaying αFuc (9A) reaches strong binding improvement (IC50 of 0.6 nM) over αMeFuc, and increases the α-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 β-fucosylated conjugates, albeit being less active than the corresponding ligands of the αFuc 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.

Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells

“…Moreover, multivalent presentation of glycans may also be better suited for patients having lower values of circulating antibodies. Therefore, we decided to synthesized tetra‐ and hexadecavalent Rha‐based ABMs (Scheme ) by using peptide carriers previously identified as well‐suited scaffolds for multivalent presentation of sugars . Starting from the tetraazido cyclodecapeptide 1 , a first CuAAC reaction with propargyl l ‐rhamnopyranoside afforded the tetravalent cluster 2 .…”

Immunological characterization of a rigid α-Tn mimetic on murine iNKT and human NK cells

“…The coupling reaction was performed with PyBOP as coupling reagent in DMF to afford the hexavalent acetylated compound that was subsequently deprotected with sodium methanoate in methanol. The resulting glycopeptide 6 was obtained in 51% yield after RP-HPLC purification Compounds 11 and 12 have been synthesized from cyclopeptide 13 [44] and α-ONH 2 -GalNAc [45][46][47][48]53] and hydroxylamine hydrochloride, respectively, using the oxime ligation strategy described earlier [46][47][48]53]. The conjugation reaction occurred in water with 0.1% of TFA and the conversion of 13 was found quantitative in both cases within 2 h at 37°C.…”

Monodisperse Sequence‐Controlled α‐l‐Fucosylated Glycooligomers and Their Multivalent Inhibitory Effects on LecB

“…LecB binding affinities could be improved by functionalizing l ‐fucose with methyl (MeFuc) or p ‐nitrophenyl groups . As LecB also binds oligosaccharides, for example, blood group antigens A, B, H, Le x and Le a , the latter with highest affinity of 210 n m , multivalent fucosylated glycoclusters, –oligomers, and –dendrimers were designed for LecB inhibition. Synthetic multivalent dendrimers and complex dendritic glycoclusters with up to 16 fucose units showed up to 86 times higher binding potency per sugar unit in comparison to MeFuc.…”

“…As LecB also binds oligosaccharides, for example, blood group antigens A, B, H, Le x and Le a , the latter with highest affinity of 210 n m , multivalent fucosylated glycoclusters, –oligomers, and –dendrimers were designed for LecB inhibition. Synthetic multivalent dendrimers and complex dendritic glycoclusters with up to 16 fucose units showed up to 86 times higher binding potency per sugar unit in comparison to MeFuc. Similar to other multivalent glycomimetic structures, effects of the scaffold, for example, in terms of its architecture and distances between the ligands, were shown to have an effect on LecB binding …”