Potent divalent inhibitors with rigid glucose click spacers for Pseudomonas aeruginosa lectin LecA

Abstract

The synthesis of a new rigid spacer based on carbohydrate-triazole repeating units and their incorporation into divalent systems is described. Inhibition studies showed that a well-matched system with a rigid spacer with flexible ends leads to the most potent inhibition of Pseudomonas aeruginosa lectin LecA.

Efficient synthesis of phenylene-ethynylene rods and their use as rigid spacers in divalent inhibitors

“…This tetrameric lectin binds galactosides and the shortest distance between two binding sites is around 26 Å [20,28]. We previously noted that the use of a rigid spacer with some flexibility in the aglycon chain connecting the galactose ligands, led to more potent inhibition [10]. Since the distance to cover is ca.…”

“…The inhibitory potency of 22 for LecA was studied in an ELISA type assay by using a glycochip as the solid phase [10]. In this assay an IC 50 value of 0.9 μM was determined (Table 1).…”

“…Examples of these have been reported in areas such as nanoelectronics and nanooptics [1], surfactants [2–4], photoelectrochemical detection [5], catalysis [6], glycosylation reactions [7], and carbohydrate–protein interactions [8]. Many different strategies and molecule types have been used depending on the desired geometry, such as ring formation [9], carbohydrate–triazole conjugation [10], aryl–alkyne linked structures [11–15] and the use of DNA as a rigid bridge between silver nanoparticles and quantum dots [5]. Among the rigid linking units the phenylene-ethynylene unit has seen considerable interest in sensor [16] and molecular-electronics applications [17].…”

“…The spacer is an important factor in the design of an effective multivalent ligand [23]. While most systems reported thus far contain flexible spacers, there is a major untapped potential for systems based on rigid spacers, even though some flexibility may be needed to overcome design imperfections [10]. …”

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

“…[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. The blood group antigen Lewis a (26), bearing a terminal α-fucoside, is the best known monovalent ligand of LecB (K d = 220 nM).…”