Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

Bruneau, Alexandre; Gillon, Émilie; Furiga, Aurélie; Brachet, Etienne; Alami, Mouâd; Roques, Christine; Varrot, A.; Messaoudi, Samir

doi:10.1016/j.ejmech.2022.115025

Cited by 3 publications

(5 citation statements)

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“…For the monovalent system, it has been shown that aromatic aglycons favored “T-shaped” CH ... π interactions with the protons of the His50 imidazole in the carbohydrate-binding pocket, with the β-linked aromatic aglycons having five-fold higher affinity compared to aliphatic analogues [ 33 – 34 ]. Beside β- O -aryl galactosides, enzymatically more stable β- S -aryl galactosides have also been successfully developed as monovalent LecA ligands ( Figure 1A ) [ 30 , 35 ]. Since different sizes and substituents are tolerated on the aryl aglycon, we decided to replace the aryl aglycon by photoswitchable azobenzene in both O - and S -galactosides ( Figure 1B ) to investigate their binding affinity and the influence of the photoisomerization on the lectin interaction.…”

Section: Resultsmentioning

confidence: 99%

“…Unfortunately, all our attempts to synthesize the o , o’ -bis-substituted derivative failed. For the β- S -galactosyl azobenzene derivatives which are accessible by our previously reported Pd-catalyzed cross-coupling methodology between glycosyl thiols and iodoaryl partners [ 30 , 38 ], the required p- , m- or o -iodo- p’ -hydroxyazobenzenes 12 , 17 , and 21 were prepared by the diazonium coupling method according to a reported procedure [ 39 – 40 ]. Then the coupling with tetra- O -acetylated β-galactosylthiol 13 catalyzed by Xantphos Pd-G 3 [ 38 ] as precatalyst followed by post-functionalization furnished the desired β- S -galactosyl azobenzenes 3 , 4 , and 5 in respectively 71%, 41%, and 37% total yields ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

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Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

Fan,

El Rhaz,

Maisonneuve

et al. 2024

Beilstein J. Org. Chem.

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Biofilm formation is one of main causes of bacterial antimicrobial resistance infections. It is known that the soluble lectins LecA and LecB, produced by Pseudomonas aeruginosa, play a key role in biofilm formation and lung infection. Bacterial lectins are therefore attractive targets for the development of new antibiotic-sparing anti-infective drugs. Building synthetic glycoconjugates for the inhibition and modulation of bacterial lectins have shown promising results. Light-sensitive lectin ligands could allow the modulation of lectins activity with precise spatiotemporal control. Despite the potential of photoswitchable tools, few photochromic lectin ligands have been developed. We have designed and synthesized several O- and S-galactosyl azobenzenes as photoswitchable ligands of LecA and evaluated their binding affinity with isothermal titration calorimetry. We show that the synthesized monovalent glycoligands possess excellent photophysical properties and strong affinity for targeted LecA with Kd values in the micromolar range. Analysis of the thermodynamic contribution indicates that the Z-azobenzene isomers have a systematically stronger favorable enthalpy contribution than the corresponding E-isomers, but due to stronger unfavorable entropy, they are in general of lower affinity. The validation of this proof-of-concept and the dissection of thermodynamics of binding will help for the further development of lectin ligands that can be controlled by light.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

Fan,

El Rhaz,

Maisonneuve

et al. 2024

Beilstein J. Org. Chem.

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“…However, direct photo modulation of monovalent lectin ligand has not been achieved up to date. Based on our experiences in photoswitchable glycosides and bacterial lectins, [4,[6][7][8][24][25][26][27][28][29] we have designed, synthesized and characterized the first generation of O-and S-galactosyl azobenzenes as photoswitchable monovalent ligands targeting PA LecA. Their binding affinity with LecA evaluated by isothermal titration calorimetry (ITC) showed Kd values in micromolar range with significant thermodynamics difference between E-and Z-azobenzene isomers, demonstrating the proofof-concept of photomodulation of the ligand-lectin interactions.…”

Section: Introductionmentioning

confidence: 90%

“…[31,32] Beside β-O-aryl galactosides, enzymatically more stable β-S-aryl galactosides have also been successfully developed as monovalent LecA ligands (Figure 1A). [28,33] Since different sizes and substituents are tolerated on the aryl aglycon, we decided to replace the aryl aglycon by photoswitchable azobenzene in both O-and S-galactosides (Figure 1B) to investigate their binding affinity and the influence of the photoisomerization on the lectin interaction. The ammonium group is introduced on the azobenzene to increase the water solubility.…”

Section: Design Of Leca Photoswitchable Ligandsmentioning

confidence: 99%

“…Unfortunately all our attempts to synthesize the o,o'-bis-substituted derivative failed. For the β-Sgalactosyl azobenzene derivatives which are accessible by our previously reported Pd-catalyzed crosscoupling methodology between glycosyl thiols and iodoaryl partners, [28,35] the required p-, m-or oiodo-p'-hydroxy-azobenzenes (12, 17 and 21) were prepared by the diazonium coupling method according to a reported procedure. [36,37] Then the coupling with tetra-O-acetylated β-galactosylthiol 13 catalysed by Xantphos Pd-G3 [35] precatalyst followed by post-functionalisation furnished the desired β-S-galactosyl azobenzenes 3-5 in 37-71% total yields (Scheme 1).…”

Section: Synthesismentioning

confidence: 99%

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Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

Fan,

El Rhaz,

Maisonneuve

et al. 2024

Preprint

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Biofilm formation is one of main causes of bacterial antimicrobial resistance infections. It is known that the soluble lectins LecA and LecB, produced by Pseudomonas aeruginosa, play a key role in biofilm formation and lung infection. Bacterial lectins are therefore attractive targets for the development of new antibiotic-sparing anti-infective drugs. Building synthetic glycoconjugates for the inhibition and modulation of bacterial lectins have shown promising results. Light-sensitive lectins ligands could allow the modulation of lectins activity with precise spatiotemporal control. Despite the potential of photoswitchable tools, few photochromic lectin ligands have been developed. We have designed and synthesized several O- and S-galactosyl azobenzenes as photoswitchable ligands of LecA and evaluated their binding affinity with isothermal titration calorimetry. We show that the synthesized monovalent glycoligands possess excellent photophysical properties and strong affinity for targeted LecA with Kd values in the micromolar range. Analysis of the thermodynamic contribution indicates that the Z-azobenzene isomers have systematically stronger favorable enthalpy contribution than the corresponding E-isomers, but due to stronger unfavorable entropy, they are in general of lower affinity. The validation of this proof-of-concept and the dissection of thermodynamics of binding will help for the further development of lectins ligands that can be controlled by light.

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Bispecific Thio‐Linked Disaccharides as Inhibitors of Pseudomonas Aeruginosa Lectins LecA (PA‐IL) and LecB (PA‐IIL): Dual‐Targeting Strategy

Faltinek,

Melicher,

Kelemen

et al. 2024

Chemistry A European J

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Pseudomonas aeruginosa is a prevalent opportunistic human pathogen, particularly associated with cystic fibrosis. Among its virulence factors are the LecA and LecB lectins. Both lectins play an important role in the adhesion to the host cells and display cytotoxic activity. In this study, we successfully synthesized hardly hydrolysable carbohydrate ligands targeting these pathogenic lectins, including two bispecific glycans. The interactions between LecA/LecB lectins and synthetic glycans were evaluated using hemagglutination (yeast agglutination) inhibition assays, comparing their efficacy with corresponding monosaccharides. Additionally, the binding affinities of bispecific glycans were assessed using isothermal titration calorimetry (ITC). Structural insight into the lectin‐ligand interaction was obtained by determining the crystal structures of LecA/LecB lectins in complex with one of the bispecific ligands using X ray crystallography. This comprehensive investigation into the inhibitory potential of synthetic glycosides against P. aeruginosa lectins sheds light on their potential application in antimicrobial therapy.

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Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

Cited by 3 publications

References 57 publications

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

Bispecific Thio‐Linked Disaccharides as Inhibitors of Pseudomonas Aeruginosa Lectins LecA (PA‐IL) and LecB (PA‐IIL): Dual‐Targeting Strategy

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