Synthesis of Dodecavalent Fullerene‐Based Glycoclusters and Evaluation of Their Binding Properties towards a Bacterial Lectin

Abstract

Multivalency is playing a major role in biological processes and particularly in lectin-carbohydrate interactions. The design of high-affinity ligands of lectins should provide molecules capable of interfering with these biological processes and potentially inhibit bacterial or viral infections. Azide-alkyne "click" chemistry was applied to the synthesis of dodecavalent fullerene-based glycoclusters. The conjugation could be efficiently performed from alkyne or azide functions on either partners (i.e. hexakis-fullerene adduct or glycoside). PA-IL is a bacterial lectin from the opportunistic pathogen Pseudomonas aeruginosa and is involved in the recognition of glycoconjugates on human tissues. The glycoclusters obtained were evaluated as ligands of PA-IL and for their potential for competing with its binding to glycosylated surfaces. The affinities measured by hemagglutination inhibition assay (HIA), enzyme-linked lectin assay (ELLA), and surface plasmon resonance (SPR) displayed a significant "glycoside cluster effect" with up to a 12,000-fold increase in binding when comparing a monovalent carbohydrate reference probe with a dodecavalent fullerene-based glycocluster, albeit with some differences depending on the analytical technique.

Clustering of Escherichia coli Type‐1 Fimbrial Adhesins by Using Multimeric Heptyl α‐D‐Mannoside Probes with a Carbohydrate Core

“…The larger the functional valency of the ligand, the larger these microclusters of FimH grow. Increasing noise levels were indeed observed in the ITC experiments from the monovalent compound 24, over the bi- (25) and trivalent (26) ligands, to the heptavalent 27 ( Figure 1 and Table 2 (c 2 / DOF )). Successive protein-protein attractions and repulsions within these microclusters could cause small heat releases and heat uptakes, respectively.…”

“…[24] Furthermore, numerous recent examples successfully report the use of CuAAC to design glycoclusters and other sugar mimetics. [25,26] Compound 2 was obtained in three synthetic steps as previously described in the literature (Scheme 2). [27] Tosylation of unprotected glucose in the C-6 position followed by acetylation of the hydroxyl groups and substitution by an azide efficiently provided gram-scale quantities of 2.…”

Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection

“…Depending upon the starting sugar derivatives employed (monomer, dimer or trimer) 12, 24 and up to 36 monosaccharides have been introduced on the periphery of the fullerene central core in a straightforward manner. 14,15,16,17 Remarkably, some of the aforementioned glycofullerenes have proven to show interesting biomedical applications. 18 Thus, a significant multivalent effect has been observed in the inhibition profile of a [60]fullerene hexakis-adduct endowed with 12 iminosugar units towards different glycosidases.…”

Cyclooctyne [60]fullerene hexakis adducts: a globular scaffold for copper-free click chemistry

“…5 On the other hand, in the area of biological applications, their activity has been tested in different fields showing interesting properties and good biocompatibility. Hexakis adducts of [60]fullerene have been tested as gene transfection vectors, 6 multiplying units for photodynamic therapy, 7 glycosidase and glycosyltransferase inhibitors, 8 or efficient antibacterial 9 or antiviral systems. 10 The synthesis of these adducts was first studied by Hirsch by the one-pot addition of malonates templated by 9,10-dimethylanthracene 11 and later modified by Sun.…”