Achieving High Affinity towards a Bacterial Lectin through Multivalent Topological Isomers of Calix[4]arene Glycoconjugates

Abstract

A family of seven topologically isomeric calix[4]arene glycoconjugates was prepared through the synthesis of a series of alkyne-derivatised calix[4]arene precursors that are suitable for the attachment of sugar moieties by microwave-assisted copper(I)-catalysed azide-alkyne cycloaddition (CuAAC). The glycoconjugates thus synthesised comprised one mono-functionalised derivative, two 1,2- or 1,3-divalent regioisomers, one trivalent and three tetravalent topoisomers in the cone, partial cone or 1,3-alternate conformations. The designed glycoconjugates were evaluated as ligands for the galactose-binding lectin PA-IL from the opportunistic bacterium Pseudomonas aeruginosa, a major causative agent of lung infections in cystic fibrosis patients. Binding affinities were determined by isothermal titration calorimetry (ITC), and the interaction with the lectin was shown to be strongly dependant on both the valence and the topology. Whereas the trivalent conjugate displayed enhanced affinity when compared to a monosaccharide model, the tetravalent conjugates are to-date the highest-affinity ligands measured by ITC. The topologies presenting carbohydrates on both faces of calixarene are the most potent ones with dissociation constants of approximately 200 nM. Molecular modelling suggests that such a multivalent molecule can efficiently chelate two of the binding sites of the tetrameric lectin; this explains the 800-fold increase of affinity achieved by the tetravalent molecule. Surface plasmon resonance (SPR) experiments confirmed that this glycoconjugate is the strongest inhibitor for binding of PA-IL to galactosylated surfaces for potential applications as an anti-adhesive agent.

Role of Water Molecules in Structure and Energetics of Pseudomonas aeruginosa Lectin I Interacting with Disaccharides

“…Considering the multivalency of lectins, the synthesis of multivalent ligands is a classical way for gaining avidity. Indeed, the first tetravalent galactose-containing ligand for PA-IL demonstrated a 850-fold increase in affinity compared with the monomeric ligand (57). Combining the detailed knowledge about the structure and energetics of the binding site together with the multivalency approach will be the route for the design of drugs active against P. aeruginosa infection.…”

Stable and sensitive probes for lysosomes: Cell‐penetrating fluorescent calix[4]arenes accumulate in acidic vesicles

“…Recently, interest has focused on the use of calixarene derivatives in biological systems be it as drugs, drug delivery systems, or imaging agents. In the design of drug molecules, particular attention has been paid to calixarenes as antimicrobials (6)(7)(8), as vaccines (9) and as anticancer agents (10). In the field of drug delivery, agents for nucleic acids based on single calixarenes (11)(12)(13) have shown promise and we have recently shown that larger arrays of cationic calix [4]arene, so-called multicalixarenes, are able to transfect DNA effectively (14).…”

Effect of cigarette smoking on serum α-L-fucose and its related parameters

“…There is a relation between Ca +2 ion concentrations and glycoconjugates in the cell. It has been published that Ca +2 ions have importance roles in both; the secretion of glycoconjugates from the cells, and the binding of lectin to glycan moieties of glycoconjugates (cell-cell adhesion and cell-environment adhesion) 34 . Thus, Ca…”

“…They were free of diabetes mellitus, hypertension, cardiovascular, and immune diseases and they have received no medications (by history taking) .There age was ranged between (20-50) years. They were classified according to the number of cigarette sticks smoked per day and the duration of smoking, into; heavy smokers (31) who used to smoke (≥20) sticks per day for ≥ 10 years, moderate smokers (26) used to smoke (10-19) sticks per day for (4-7) years, passive smokers (30) who are non-smokers, but living with smokers 23 , and finally non-smokers (control) (34) who are non-smokers and living with non-smokers. About (10) ml of blood was withdrawn from each volunteer, and then it was collected in a container with no anticoagulant.…”