Synthesis and binding properties of divalent and trivalent clusters of the Lewis a disaccharide moiety to Pseudomonas aeruginosa lectin PA-IIL

Abstract

The synthesis of oligomeric glycocomimetics has been performed for targeting the Pseudomonas aeruginosa PA-IIL lectin, which is of therapeutical interest for anti-adhesive treatment. The disaccharide alpha-L-Fucp-(1-->4)-beta-D-GlcNAc, which is a high-affinity ligand of the lectin, has been coupled to dimeric and trimeric linkers with various lengths and geometries. A series of linear dimers displayed an efficient clustering effect and a very strong affinity, with a lower dissociation constant of 90 nM. The trimeric compound was less efficient in inhibition assays but displayed high affinity in solution. Titration microcalorimetry and molecular modeling allowed in-depth analysis and rationalization of the binding data. These glycoclusters could act by crosslinking the lectins present on the surface of bacteria and therefore interfere with host recognition or biofilm formation.

Glycomimetics and Glycodendrimers as High Affinity Microbial Anti‐adhesins

“…Binding data for PA-IIL interacting with different carbohydrates, glycomimetics, and glycopolymers. l-Fuc 2.9 10 3 À7.5 1 [20] Me-a-Man 71 10 3 À5.7 0.04 [49] Me-a-Fuc 430 À8.7 6.7 [49] Lewis a 210 À9.1 13.8 [20] 20 310 À8.9 9.3 [19] 21 290 À8.9 10 [19] 22 170 À9.2 17 40 8.5 À20 [a] [39] 23 90 À9.6 32 16 [39] 24 100 À9.5 29 9.7 [39] 33 22.4 2.2 [42] 34 3.5 1.7 [43] 35 29 7.2 [43] 36 80 20 [44] [a] Values from ITC and ELLA, respectively.…”

“…The second generation of ligands (22-24) contain 2 or 3 high affinity aFuc1-4GlcNAc disaccharides connected through linkers of various lengths and geometries. [39] Among them, the linear and flexible compound 23 displays the highest affinity (K d = 90 nm), as observed from titration microca- lorimetry. At low concentration of the ligand, a PA-IIL/ ligand stoichiometry of 2:1 is observed, followed by precipitation at higher concentration, indicating that this divalent ligand is an efficient clustering agent.…”

Role of LecA and LecB Lectins in Pseudomonas aeruginosa -Induced Lung Injury and Effect of Carbohydrate Ligands

“…Administration of specific lectin inhibitors was remarkably effective. The elucidation of the crystal structures of P. aeruginosa lectins complexed with carbohydrate ligands (5,23), together with a synthetic chemistry effort to produce high-affinity carbohydrate-based ligands (21,22), opens new possibilities for lectins as novel therapeutic targets in P. aeruginosa infections.…”

From carbohydrate leads to glycomimetic drugs

“…Oligovalent forms of the Fucα (14)GlcNAc epitope, such as compound 14 (REF. 102), exhibit increased activity compared with monovalent forms; however, in most cases, this effect was only modest on a per saccharide basis. To date, multivalency has only been explored with dendri mers that present lfucose, which show an increase in affinity of up to a factor of 20 on a per saccha ride basis 103 .…”