Synthesis of Galabiose-chitosan Conjugate as Potent Inhibitor of Streptococcus suis Adhesion

Abstract

The aim of this work is to construct a safe and effective drug candidate against Streptococcus suis infection. A panel of chitosan-based polymer conjugates with branched galabiose (Galalpha1-4Gal) side chains was synthesized as inhibitors of S. suis adhesion. The synthesis was achieved by using an aldehyde-functionalized galabiose derivative to graft it onto chitosan amino groups. Structural compositions of the conjugates were verified by 1H NMR spectroscopy and CHN elemental analyses. Potent inhibitory activities of the conjugates against S. suis adhesion to human erythrocytes were determined at low nanomolar concentration by HAI assay. An SPR study revealed a high affinity binding (Kd=39.6 nM) of the conjugate with BSI-B4 lectin. By using biocompatible chitosan as the scaffold for presenting S. suis -specific galabiose units, as well as the concise route tailored for the conjugate syntheses, the present study provides a practical way for explorations of new anti- S. suis therapies.

Structural basis of the interaction between the meningitis pathogen Streptococcus suis adhesin Fhb and its human receptor

“…Specific antibodies against Fhb were also detected in patients infected with S. suis 2 [15]. Multivalent Gb2 derivatives have been constructed as drug candidates against S. suis infection [32][33][34][35]. Our report on the structure of the complex of Fhb RBD bound to Gb2 provides structural insights into the Fhbmediated bacterial and receptor interactions, and will guide the development of more effective antiadhesion drugs against S. suis infection.…”

Synthesis and Assessment of Globotriose–Chitosan Conjugate, a Novel Inhibitor of Shiga Toxins Produced by Escherichia coli

“…Purification of the residue by MPLC (5:1 ethyl acetate/n-hexane) yielded compound 9 as a white powdery material (5.8 g, 70%). 1 (10). To a solution of compound 9 (5.7 g, 8.98 mmol) in dry pyridine (80 mL) at −20 °C was added dropwise acetyl chloride (665 μL, 9.36 mmol).…”

“…21,22 In addition to the synthetic agents, engineered bacteria displaying globotriose mimics on their surface have also been demonstrated as excellent Stx neutralizers, offering complete protection against lethal toxin doses in mice. 23,24 Extending our work on the development of chitosan-based anti-infective agents, 9,10 we have undertaken the synthesis and bioevaluation of GC 1 as a new class of molecule that targets the Stx− globotriose interaction. Chitosan has been widely employed as the carrier of proteins, nucleic acids, and drugs, especially in the medical and pharmaceutical fields.…”

“…The natural polysaccharide chitosan presents, from a pharmacological viewpoint, an ideal scaffold molecule because of its high biocompatibility, biodegradability, and antibacterial activity. − Combining glycoligands with chitosan exhibiting diverse bioactivities could generate safe and practical agents for pharmaceutical and medical use. We have previously developed a set of chitosan conjugates displaying specific carbohydrate sequences on their backbones that appear to antagonize influenza virus hemagglutinin, Streptococcus suis adhesins, and E-selectin. − Here we present the synthesis and structural characterization of a new member of this group bearing trisaccharide globotriose (globotriose–chitosan conjugate (GC 1 ), Chart ). We also demonstrate the potential of the new conjugate to neutralize Shiga toxin (Stx) and to treat Stx-producing Escherichia coli (STEC) infection.…”

Synthetic Fluorescent Nanoplatform Based on Benzoxaborole for Broad-Spectrum Inhibition of Bacterial Adhesion to Host Cells

“…Since recognition and attachment of pathogenic bacteria to host tissues are generally driven by the interactions between bacterial surface proteins and complementary carbohydrate receptors presented at the host cell periphery, conventional antiadhesive agents usually acting as glycomimetics are designed to block the microbial adhesion pathway in a competition mechanism. , Considering the low affinity of monosaccharide for bacterial proteins, multivalent glycosylated macromolecules including glycoclusters, glycopolymers, glycodendrimers, , glyconanoparticles, and multivalent nanofibers have recently been developed as novel inhibitors to potentially protect the host cells from bacterial infections. For example, Boukerb et al synthesized an antiadhesive glycocluster decorated with galactosides or fucosides against Pseudomonas aeruginosa (PA) lung infection utilizing the specific binding of galactose and fucose to LecA and LecB in P.…”