Optimizing Divalent Inhibitors of <i>Pseudomonas aeruginosa</i> Lectin LecA by Using A Rigid Spacer

Pertici, Francesca; Mol, Nico J. de; Kemmink, Johan; Pieters, Roland J.

doi:10.1002/chem.201303463

Cited by 65 publications

(116 citation statements)

References 27 publications

(21 reference statements)

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“…[2,3] It was demonstrated in a P. aeruginosa model of infection that the lectin is involved in lung injury and mortality [4][5][6][7] and recent data suggested that LecA promotes bacterial invasion into host cells. [9,15] These studies clearly highlighted the potential benefit of oligovalent interactions since dissociation constants lower than 90 nm and 20 nm were obtained for tetravalent [11,16] and divalent [13] compounds, respectively. 30 .…”

mentioning

confidence: 80%

“…[1] In the case of P. aeruginosa, the structural basis for the preference of the LecA lectin towards galactose and globotriaosylceramide (Gb3) was elucidated. This structural knowledge has stimulated intense work to design templates presenting galactose residues with a spacing that matches the dimeric geometry of LecA neighboring binding sites [8][9][10][11][12][13][14][15][16] with the potential of acting as anti-pathogenic agents [17,18] or disrupting biofilm formation. [7] The lectin is a tetramer and structural data demonstrated an overall rectangular shape with pairing of neighboring binding sites separated by ca.…”

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confidence: 99%

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A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

et al. 2014

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Lectin LecA is a virulence factor of Pseudomonas aeruginosa involved in lung injury, mortality, and cellular invasion. Ligands competing with human glycoconjugates for LecA binding are thus promising candidates to counteract P. aeruginosa infections. We have identified a novel divalent ligand from a focused galactoside(Gal)-conjugate array which binds to LecA with very high affinity (Kd = 82 nM). Crystal structures of LecA complexed with the ligand together with modeling studies confirmed its ability to chelate two binding sites of LecA. The ligand lowers cellular invasiveness of P. aeruginosa up to 90 % when applied in the range of 0.05-5 μM. Hence, this ligand might lead to the development of drugs against P. aeruginosa infection.

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confidence: 80%

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confidence: 99%

A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

et al. 2014

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“…Despite its seeming simplicity, the rational design of divalent ligands is still challenging [16–19]. In this paper we examine a general model for a divalent receptor–ligand system in order to estimate the binding affinity from the dissociation constant of the monovalent ligand and the length and flexibility of the ligand spacer.…”

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confidence: 99%

Influence of length and flexibility of spacers on the binding affinity of divalent ligands

Liese¹,

Netz²

2015

Beilstein J. Org. Chem.

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SummaryWe present a quantitative model for the binding of divalent ligand–receptor systems. We study the influence of length and flexibility of the spacers on the overall binding affinity and derive general rules for the optimal ligand design. To this end, we first compare different polymeric models and determine the probability to simultaneously bind to two neighboring receptor binding pockets. In a second step the binding affinity of divalent ligands in terms of the IC50 value is derived. We find that a divalent ligand has the potential to bind more efficiently than its monovalent counterpart only, if the monovalent dissociation constant is lower than a critical value. This critical monovalent dissociation constant depends on the ligand-spacer length and flexibility as well as on the size of the receptor. Regarding the optimal ligand-spacer length and flexibility, we find that the average spacer length should be equal or slightly smaller than the distance between the receptor binding pockets and that the end-to-end spacer length fluctuations should be in the same range as the size of a receptor binding pocket.

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“…This spacer was capped with two galactose monosaccharides and assayed against LecA as a multivalent chelate inhibitor. Interestingly, the size and the rigidity of the linker was important for optimum IC 50 and could thereby be tuned for selectivity between different lectins [46–48]. …”

Section: Non-natural Sugars As Linkersmentioning

confidence: 99%

Designing sugar mimetics: non-natural pyranosides as innovative chemical tools

Saliba

Pohl

2016

Current Opinion in Chemical Biology

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The importance of oligosaccharides in myriad biological processes are becoming increasingly clear. However, these carbohydrate-mediated processes are often challenging to dissect due to the often poor affinity, stability and selectivity of the oligosaccharides involved. To circumvent these issues, non-natural carbohydrates—carbohydrate mimics—are being designed as innovative tools to modify biomolecules of interest or to understand biological pathways using fluorescence microscopy, X-ray or nuclear magnetic resonance spectroscopy (NMR). This review focuses on key examples of recently developed non-natural sugars to answer specific biological needs.

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Optimizing Divalent Inhibitors of Pseudomonas aeruginosa Lectin LecA by Using A Rigid Spacer

Cited by 65 publications

References 27 publications

A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

Influence of length and flexibility of spacers on the binding affinity of divalent ligands

Designing sugar mimetics: non-natural pyranosides as innovative chemical tools

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