Rational Design and Synthesis of Optimized Glycoclusters for Multivalent Lectin–Carbohydrate Interactions: Influence of the Linker Arm

Abstract

The design of multivalent glycoclusters requires the conjugation of biologically relevant carbohydrate epitopes functionalized with linker arms to multivalent core scaffolds. The multigram-scale syntheses of three structurally modified triethyleneglycol analogues that incorporate amide moiety(ies) and/or a phenyl ring offer convenient access to a series of carbohydrate probes with different water solubilities and rigidities. Evaluation of flexibility and determination of preferred conformations were performed by conformational analysis. Conjugation of the azido-functionalized carbohydrates with tetra-propargylated core scaffolds afforded a library of 18 tetravalent glycoclusters, in high yields, by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The compounds were evaluated for their ability to bind to PA-IL (the LecA lectin from the opportunistic pathogen Pseudomonas aeruginosa). Biochemical evaluation through inhibition of hemagglutination assays (HIA), enzyme-linked lectin assays (ELLA), surface plasmon resonance (SPR), and isothermal titration microcalorimetry (ITC) revealed improved and unprecedented affinities for one of the monovalent probes (K(d)=5.8 μM) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin.

Biologically Active Heteroglycoclusters Constructed on a Pillar[5]arene‐Containing [2]Rotaxane Scaffold

“…The tetrameric structure presents the binding sites in opposite orientation in space14b and therefore this particular lectin is also not very sensitive to multivalent effects 16. In the particular case of 21 , a significant decrease in affinity is even observed when compared to monovalent ligand α‐FucOMe thus suggesting that negative steric effects are certainly playing a role for the binding of fucose moieties of decavalent compound 21 to LecB.…”

“…These compounds were compared to [2]rotaxanes 22 and 23 displaying only carbohydrate stoppers and to monovalent references β‐GalOMe (methyl‐β‐ d ‐galactopyranoside)14 and α‐FucOMe (methyl‐α‐ l ‐fucopyranoside) 15. The ITC data are summarized in Table 1.…”

“…Fucolectin LecB has a unique mode of binding involving two bridging calcium ions and thus a high affinity for monovalent fucose derivatives such as α‐FucOMe 14a. The tetrameric structure presents the binding sites in opposite orientation in space14b and therefore this particular lectin is also not very sensitive to multivalent effects 16.…”

Design and syntheses of mono and multivalent mannosyl-lipoconjugates for targeted liposomal drug delivery

“…Recently, it has been reported that novel mannoside glycolipid conjugates micelles are able to inhibit human immunodeficiency virus type 1 trans-infection mediated by human dendritic cells (Dehuyaser et al, 2012;Schaffer et al, 2013). Several multivalent galactosylated glycoclusters that incorporated analogues of triethyleneglycol as a linker arm were prepared (Cecioni et al, 2012). The selected structures comprised one or two amide groups, as well as phenyl aromatic ring, in a triethyleneglycol moiety to achieve increased rigidity of the chain.…”

New Approaches to Control Infections: Anti-biofilm Strategies against Gram-negative Bacteria

“…24, 25). [61][62][63] Pieters et al reported bivalent galactosides which are thought to bind simultaneously to two of the four carbohydrate binding sites of LecA as concluded from the high potency (IC 50 = 220 nM). [64] LecB displays an unusually strong affinity for α-fucosides in the high nanomolar range, which could be explained by the crystal structure of the complex: [65] the presence of two calcium ions in the binding site and an additional lipophilic contact of the methyl group contribute to the strong binding.…”