Switch-on Luminescent Sensing of Unlabelled Bacterial Lectin by Terbium(iii) Glycoconjugate Systems

Interactions of lectins with glycoconjugate-terbium(III) self-assembly complexes lead to sensing through enhanced lanthanide luminescence. This glycan-directed sensing paradigm detects an unlabelled lectin (LecA) associated with pathogen P. aeruginosa in solution, without any bactericidal activity. Further development of these probes could have potential as a diagnostic tool

A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate

Chronic infections with Pseudomonas aeruginosa are associated with the formation of bacterial biofilms. The tetrameric P. aeruginosa lectin LecA is a virulence factor and an anti-biofilm drug target. Increasing the overall binding affinity by multivalent presentation of binding epitopes can enhance the weak carbohydrate–ligand interactions. Lownanomolar divalent LecA ligands/inhibitors with up to 260-fold valency-normalized potency boost and excellent selectivity over human galectin-1 were synthesized from D-galactose pentaacetate and benzaldehyde-based linkers in four linear steps

Data for Morphological and reproductive analyses

Populations caught in April 2015 were female dominated and characterized with rapid reproduction, since all samples were already mature. The GSI, absolute and relative number of oocytes, and the size of oocytes were significantly different compared to all native as well as non-native areas of occurrence. The smallest mature female reached 26.27 mm, while the mean SL was 41.08 mm between all populations. Samples were characterized with three size groups of oocytes, and the biggest reached oocyte size was 1.46 mm. The absolute as well as relative number of oocytes was higher compared to other studies from native, and non-native areas of occurrence. There was no significant difference in the condition between females and males within each population, thus they were both in good and/or bad condition. Majority of traits were statistically significant, while more than a half can be suggested to have biological importance. Significant differences were related to characters located on the head, fins and associated with the length or height of the body.</p

Lectin antagonists in infection, immunity, and inflammation.

Lectins are proteins found in all domains of life with a plethora of biological functions, especially in the infection process, immune response, and inflammation. Targeting these carbohydrate-binding proteins is challenged by the fact that usually low affinity interactions between lectin and glycoconjugate are observed. Nature often circumvents this process through multivalent display of ligand and lectin. Consequently, the vast majority of synthetic antagonists are multivalently displayed native carbohydrates. At the cost of disadvantageous pharmacokinetic properties and possibly a reduced selectivity for the target lectin, the molecules usually possess very high affinities to the respective lectin through ligand epitope avidity. Recent developments include the advent of glycomimetic or allosteric small molecule inhibitors for this important protein class and their use in chemical biology and drug research. This evolution has culminated in the transition of the small molecule GMI-1070 into clinical phase III. In this opinion article, an overview of the most important developments of lectin antagonists in the last two decades with a focus on the last five years is give

Lectin antagonists in infection, immunity, and inflammation.

Lectins are proteins found in all domains of life with a plethora of biological functions, especially in the infection process, immune response, and inflammation. Targeting these carbohydrate-binding proteins is challenged by the fact that usually low affinity interactions between lectin and glycoconjugate are observed. Nature often circumvents this process through multivalent display of ligand and lectin. Consequently, the vast majority of synthetic antagonists are multivalently displayed native carbohydrates. At the cost of disadvantageous pharmacokinetic properties and possibly a reduced selectivity for the target lectin, the molecules usually possess very high affinities to the respective lectin through ligand epitope avidity. Recent developments include the advent of glycomimetic or allosteric small molecule inhibitors for this important protein class and their use in chemical biology and drug research. This evolution has culminated in the transition of the small molecule GMI-1070 into clinical phase III. In this opinion article, an overview of the most important developments of lectin antagonists in the last two decades with a focus on the last five years is give

Directing Drugs to Bugs: Antibiotic-Carbohydrate Conjugates Targeting Biofilm-Associated Lectins of Pseudomonas aeruginosa .

Chronic infections by Pseudomonas aeruginosa are characterized by biofilm formation, which effectively enhances resistance toward antibiotics. Biofilm-specific antibiotic delivery could locally increase drug concentration to break antimicrobial resistance and reduce the drug's peripheral side effects. Two extracellular P. aeruginosa lectins, LecA and LecB, are essential structural components for biofilm formation and thus render a possible anchor for biofilm-targeted drug delivery. The standard-of-care drug ciprofloxacin suffers from severe systemic side effects and was therefore chosen for this approach. We synthesized several ciprofloxacin-carbohydrate conjugates and established a structure-activity relationship. Conjugation of ciprofloxacin to lectin probes enabled biofilm accumulation in vitro, reduced the antibiotic's cytotoxicity, but also reduced its antibiotic activity against planktonic cells due to a reduced cell permeability and on target activity. This work defines the starting point for new biofilm/lectin-targeted drugs to modulate antibiotic properties and ultimately break antimicrobial resistance

Red operculum spots, body size, maturation and evidence for a satellite male phenotype in non-native European populations of pumpkinseed Lepomis gibbosus

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A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate.

Chronic infections with Pseudomonas aeruginosa are associated with the formation of bacterial biofilms. The tetrameric P. aeruginosa lectin LecA is a virulence factor and an anti-biofilm drug target. Increasing the overall binding affinity by multivalent presentation of binding epitopes can enhance the weak carbohydrate-ligand interactions. Low-nanomolar divalent LecA ligands/inhibitors with up to 260-fold valency-normalized potency boost and excellent selectivity over human galectin-1 were synthesized from d-galactose pentaacetate and benzaldehyde-based linkers in four linear steps

Neutralizing the Impact of the Virulence Factor LecA from Pseudomonas aeruginosa on Human Cells with New Glycomimetic Inhibitors

International audienceBacterial adhesion, biofilm formation and host cell invasion of the ESKAPE pathogen Pseudomonas aeruginosa require the tetravalent lectins LecA and LecB, which are therefore drug targets to fight these infections. Recently, we have reported highly potent divalent galactosides as specific LecA inhibitors. However, they suffered from very low solubility and an intrinsic chemical instability due to two acylhydrazone motifs, which precluded further biological evaluation. Here, we isosterically substituted the acylhydrazones and systematically varied linker identity and length between the two galactosides necessary for LecA binding. The optimized divalent LecA ligands showed improved stability and were up to 5000-fold more soluble. Importantly, these properties now enabled their biological characterization. The lead compound L2 potently inhibited LecA binding to lung epithelial cells, restored wound closure in a scratch assay and reduced the invasiveness of P. aeruginosa into host cells