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1.
Chem Soc Rev ; 50(12): 7330-7332, 2021 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-34109331

RESUMEN

Correction for 'Fluorescent glycoconjugates and their applications' by Baptiste Thomas et al., Chem. Soc. Rev., 2020, 49, 593-641, DOI: 10.1039/C8CS00118A.

2.
Chem Soc Rev ; 49(2): 593-641, 2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31915764

RESUMEN

Glycoconjugates and their applications as lectin ligands in biology have been thoroughly investigated in the past decades. Meanwhile, the intrinsic properties of such multivalent molecules were limited essentially to their ability to bind to their receptors with high selectivity and/or avidity. The present review will focus on multivalent glycoconjugates displaying an additional capability such as fluorescence properties not only for applications toward imaging of cancer cells and detection of proteins or pathogens but also for drug delivery systems toward targeted cancer therapy. This review is a collection of research articles discussed in the context of the structural features of fluorescent glycoconjugates organized according to their fluorescent core scaffold and with their representative applications.


Asunto(s)
Colorantes Fluorescentes/química , Glicoconjugados/química , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Fluorescencia , Humanos , Neoplasias/tratamiento farmacológico
3.
Chemistry ; 26(63): 14445-14452, 2020 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-32864796

RESUMEN

Two red-emitting dicyanomethylene-4H-pyran (DM) based fluorescent probes were designed and used for peroxynitrite (ONOO- ) detection. Nevertheless, the aggregation-caused quenching effect diminished the fluorescence and restricted their further applications. To overcome this problem, tetraphenylethylene (TPE) based glycoclusters were used to self-assemble with these DM probes to obtain supramolecular water-soluble glyco-dots. This self-assembly strategy enhanced the fluorescence intensity, leading to an enhanced selectivity and activity of the resulting glyco-dot comparing to DM probes alone in PBS buffer. The glyco-dots also exhibited better results during fluorescence sensing of intracellular ONOO- than the probes alone, thereby offering scope for the development of other similar supramolecular glyco-systems for chemical biological studies.


Asunto(s)
Colorantes Fluorescentes , Imagen Óptica , Ácido Peroxinitroso , Piranos , Estilbenos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/normas , Glicoconjugados/química , Imagen Óptica/métodos , Ácido Peroxinitroso/análisis , Piranos/química , Estilbenos/química
4.
Org Biomol Chem ; 18(5): 931-940, 2020 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-31922157

RESUMEN

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Glucosa/metabolismo , Glucógeno Fosforilasa/antagonistas & inhibidores , Hipoglucemiantes/farmacología , Compuestos de Espiro/farmacología , Tiazoles/farmacología , Animales , Glucemia/metabolismo , Ciclización , Teoría Funcional de la Densidad , Glucógeno/metabolismo , Glucógeno Fosforilasa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Concentración 50 Inhibidora , Cinética , Lactonas/síntesis química , Lactonas/química , Oxidación-Reducción , Ratas Zucker , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Estereoisomerismo , Temperatura , Tiazoles/síntesis química , Tiazoles/química
5.
Bioorg Chem ; 98: 103713, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32151966

RESUMEN

A series of novel isoxazolidines based on benzaldehyde derivatives have been synthesized from the cycloaddition of chiral menthone-based nitrone and allyl phenyl ethers. All synthetic compounds were assessed for their in vitro PPA, HPA and HLAG inhibitory activity. The results revealed that all targets exhibited better inhibitory effect against PPA (12.3 ± 0.4 < IC50 < 38.2 ± 0.9 µM), HPA (10.1 ± 0.4 < IC50 < 26.8 ± 0.2 µM) and HLAG (65.4 ± 1.2 < IC50 < 274.8 ± 1.1 µM) when compared with the reference inhibitor, acarbose (IC50 = 284.6 ± 0.3 µM for PPA, 296.6 ± 0.8 µM for HPA, 780.4 ± 0.3 µM for HLAG) with the highest PPA inhibitory activity was ascribed to compound 3g against both PPA and HPA, and 3b against HLAG enzymes, respectively. Structural activity relationships (SARs) were also established for all synthesized compounds and the interaction modes of the most potent inhibitors (3g for PPA and HPA, 3b for HLAG) and the active site with residues of three enzymes were confirmed through molecular docking studies. Furthermore, a combination of molecular docking analysis with the in vitro activities can help to improve prediction success and encourages the uses of some of these molecules as potential alternatives toward the modulation of T2D.


Asunto(s)
Inhibidores de Glicósido Hidrolasas/farmacología , Isoxazoles/farmacología , alfa-Amilasas/antagonistas & inhibidores , alfa-Glucosidasas/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Páncreas/enzimología , Relación Estructura-Actividad , Porcinos , alfa-Amilasas/metabolismo
6.
Appl Opt ; 59(24): 7390-7395, 2020 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-32902507

RESUMEN

We report a full experimental comparison study on the injection of a Ti:Sa multi-terawatt amplifier chain with a standard 15 fs Ti:Sa oscillator and 35 fs frequency-doubled fiber oscillator. The study highlights that the Ti:Sa oscillator, with high performance in terms of pulse duration and spectral width, can be replaced by the frequency-doubled fiber oscillator to seed Ti:Sa amplifier chains almost without any compromise on the output pulse duration and picosecond contrast. Finally, we demonstrate for the first time to our knowledge a 30 TW and 33 fs Ti:Sa amplifier injected by a fiber oscillator.

7.
Soft Matter ; 15(36): 7211-7218, 2019 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-31475271

RESUMEN

Pseudomonas aeruginosa is a human opportunistic pathogen responsible for lung infections in cystic fibrosis patients. The emergence of resistant strains and its ability to form a biofilm seem to give a selective advantage to the bacterium and thus new therapeutic approaches are needed. To infect the lung, the bacterium uses several virulence factors, like LecA lectins. These proteins are involved in bacterial adhesion due to their specific interaction with carbohydrates of the host epithelial cells. The tetrameric LecA lectin specifically binds galactose residues. A new therapeutic approach is based on the development of highly affine synthetic glycoclusters able to selectively link with LecA to interfere with the natural carbohydrate-LecA interaction. In this study, we combined atomic force microscopy imaging and molecular dynamics simulations to visualize and understand the arrangements formed by LecA and five different glycoclusters. Our glycoclusters are small scaffolds characterized by a core and four branches, which terminate in a galactose residue. Depending on the nature of the core and the branches, the glycocluster-lectin interaction can be modulated and the affinity increased. We show that glycocluster-LecA arrangements highly depend on the glycocluster architecture: the core influences the rigidity of the geometry and the directionality of the branches, whereas the nature of the branch determines the compactness of the structure and the ease of binding.


Asunto(s)
Carbohidratos/química , Lectinas/química , Microscopía de Fuerza Atómica/métodos , Nanoestructuras/química , Adhesión Bacteriana/efectos de los fármacos , Simulación por Computador , Células Epiteliales/efectos de los fármacos , Humanos , Modelos Moleculares , Método de Montecarlo , Unión Proteica/efectos de los fármacos , Conformación Proteica , Multimerización de Proteína , Pseudomonas aeruginosa , Termodinámica
8.
Org Biomol Chem ; 17(41): 9251-9256, 2019 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-31584602

RESUMEN

We describe a novel green-emitting tetraphenylethylene-dicyanomethylene-4H-pyran (TPE-DCM) based fluorescent probe (TD-1). Conjugating TPE and DCM moieties allowed TD-1 to display high selectivity for thiophenol with excellent AIE properties in aqueous solution. Nevertheless, the poor water solubility of the hydrophobic structure resulted in a weak and unstable emission intensity. The non-covalent self-assembly of TD-1 with a TPE glycocluster (TPE2S) led to a largely improved water solubility producing a reliable and stable sensing system. The corresponding glyco-probe could sensitively detect exogenous thiophenol concentrations in PBS buffer or environmental water samples.

9.
Chem Rev ; 117(3): 1687-1764, 2017 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-28121130

RESUMEN

This Review summarizes close to 500 primary publications and surveys published since 2000 about the syntheses and diverse bioactivities of C-glycopyranosyl (het)arenes. A classification of the preparative routes to these synthetic targets according to methodologies and compound categories is provided. Several of these compounds, regardless of their natural or synthetic origin, display antidiabetic properties due to enzyme inhibition (glycogen phosphorylase, protein tyrosine phosphatase 1B) or by inhibiting renal sodium-dependent glucose cotransporter 2 (SGLT2). The latter class of synthetic inhibitors, very recently approved as antihyperglycemic drugs, opens new perspectives in the pharmacological treatment of type 2 diabetes. Various compounds with the C-glycopyranosyl (het)arene motif were subjected to biological studies displaying among others antioxidant, antiviral, antibiotic, antiadhesive, cytotoxic, and glycoenzyme inhibitory effects.


Asunto(s)
Hidrocarburos/química , Hipoglucemiantes/farmacología , Glicosilación
10.
Molecules ; 24(24)2019 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-31835851

RESUMEN

The Photorhabdus species is a Gram-negative bacteria of the family Morganellaceae that is known for its mutualistic relationship with Heterorhabditis nematodes and pathogenicity toward insects. This study is focused on the characterization of the recombinant lectin PLL3 with an origin in P. laumondii subsp. laumondii. PLL3 belongs to the PLL family of lectins with a seven-bladed ß-propeller fold. The binding properties of PLL3 were tested by hemagglutination assay, glycan array, isothermal titration calorimetry, and surface plasmon resonance, and its structure was determined by X-ray crystallography. Obtained data revealed that PLL3 binds similar carbohydrates to those that the other PLL family members bind, with some differences in the binding properties. PLL3 exhibited the highest affinity toward l-fucose and its derivatives but was also able to interact with O-methylated glycans and other ligands. Unlike the other members of this family, PLL3 was discovered to be a monomer, which might correspond to a weaker avidity effect compared to homologous lectins. Based on the similarity to the related lectins and their proposed biological function, PLL3 might accompany them during the interaction of P. laumondii with both the nematode partner and the insect host.


Asunto(s)
Lectinas/química , Lectinas/metabolismo , Photorhabdus/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Calorimetría , Cristalografía por Rayos X , Fructosa/metabolismo , Lectinas/genética , Estructura Secundaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Resonancia por Plasmón de Superficie
11.
Chemistry ; 24(17): 4436-4444, 2018 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-29338100

RESUMEN

Calix[4]arenes are unique macrocycles that through judicious functionalisation at the lower rim can be either fixed in one of four conformations or remain conformationally flexible. Introduction of propynyl or propenyl groups unexpectedly provides a new possibility; a unidirectional conformational switch, with the 1,3-alternate and 1,2-alternate conformers switching to the partial cone conformation, whilst the cone conformation is unchanged, under standard experimental conditions. Using 1 H NMR kinetic studies, rates of switching have been shown to be dependent on the starting conformation, upper-rim substituent, where reduction in bulk enables faster switching, solvent and temperature with 1,2-alternate conformations switching fastest. Ab initio calculations (DFT) confirmed the relative stabilities of the conformations and point towards the partial cone conformer being the most stable of the four. The potential impact on synthesis through the "click" reaction has been investigated and found not to be significant.

12.
Org Biomol Chem ; 16(45): 8804-8809, 2018 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-30403242

RESUMEN

Tetraphenylethylene (TPE) is fluorescent through aggregation induced emission (AIE) in water. Herein, TPE was used as the core of glycoclusters that target the bacterial lectins LecA and LecB of Pseudomonas aeruginosa. Synthesis of these TPE-based glycoclusters was accomplished by using azide-alkyne "click" chemistry. The AIE properties of the resulting glycoclusters could be readily verified, but imaging could not be pursued due to the overlap of the fluorescence signals from cells and bacteria. Nonetheless, the glycoclusters displayed nanomolar affinities toward LecA and LecB. Further evaluation in a cell-based anti-adhesive assay highlighted a limited decrease in adhesion (20%) for the fucosylated glycocluster. This confirmed that these TPE-based glycoclusters are indeed LecA and LecB high-affinity ligands. Nevertheless, the hypotheses involving their application in imaging or anti-adhesive therapy could not be verified.


Asunto(s)
Adhesinas Bacterianas/metabolismo , Oligosacáridos/química , Oligosacáridos/metabolismo , Estilbenos/química , Ligandos , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta
13.
Chembiochem ; 18(11): 1036-1047, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28318079

RESUMEN

Lectin A (LecA) from Pseudomonas aeruginosa is an established virulence factor. Glycoclusters that target LecA and are able to compete with human glycoconjugates present on epithelial cells are promising candidates to treat P. aeruginosa infection. A family of 32 glycodendrimers of generation 0 and 1 based on a bifurcated bis-galactoside motif have been designed to interact with LecA. The influences both of the central multivalent core and of the aglycon of these glycodendrimers on their affinity toward LecA have been evaluated by use of a microarray technique, both qualitatively for rapid screening of the binding properties and also quantitatively (Kd ). This has led to high-affinity LecA ligands with Kd values in the low nanomolar range (Kd =22 nm for the best one).


Asunto(s)
Adhesinas Bacterianas/metabolismo , Diseño de Fármacos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/química , Dendrímeros/metabolismo , Células Epiteliales/química , Glicoconjugados/uso terapéutico , Humanos , Lectinas/metabolismo , Ligandos , Unión Proteica , Factores de Virulencia/metabolismo
14.
Chemistry ; 23(71): 18057-18065, 2017 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-29024190

RESUMEN

Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for ß-1,4-galactosyltransferase 7 (ß4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for ß4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-ß-xylopyranoside in the d-configuration proved to be a good substrate for ß4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable π-π interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.


Asunto(s)
N-Acetil-Lactosamina Sintasa/metabolismo , Compuestos de Sulfhidrilo/química , Xilosa/análogos & derivados , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Humanos , Cinética , Conformación Molecular , Simulación del Acoplamiento Molecular , N-Acetil-Lactosamina Sintasa/química , Resonancia Magnética Nuclear Biomolecular , Teoría Cuántica , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Especificidad por Sustrato , Compuestos de Sulfhidrilo/metabolismo , Xilosa/metabolismo
15.
Org Biomol Chem ; 15(47): 10037-10043, 2017 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-29165489

RESUMEN

The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with Kd values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti-adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed. The fluorescence properties of the PDI core were then investigated by confocal microscopy on cell-bacteria cultures. However, the red fluorescence signal of the PDI-based glycocluster was too weak to provide significant data. The present study provides another type of anti-adhesive glycocluster against bacterial infection with a large aromatic PDI core.


Asunto(s)
Adhesinas Bacterianas/efectos de los fármacos , Glicoconjugados/farmacología , Imidas/farmacología , Lectinas/antagonistas & inhibidores , Perileno/análogos & derivados , Pseudomonas aeruginosa/efectos de los fármacos , Sitios de Unión/efectos de los fármacos , Calorimetría , Adhesión Celular/efectos de los fármacos , Glicoconjugados/síntesis química , Glicoconjugados/química , Imidas/síntesis química , Imidas/química , Ligandos , Estructura Molecular , Perileno/síntesis química , Perileno/química , Perileno/farmacología , Pseudomonas aeruginosa/química , Pseudomonas aeruginosa/citología
16.
Chemistry ; 22(9): 2955-63, 2016 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-26845383

RESUMEN

The synthesis of pillar[5]arene-based glycoclusters has been readily achieved by CuAAC conjugations of azido- and alkyne-functionalized precursors. The lectin binding properties of the resulting glycosylated multivalent ligands have been studied by at least two complementary techniques to provide a good understanding. Three lectins were selected from bacterial pathogens based on their potential therapeutic applications as anti-adhesives, namely LecA and LecB from Pseudomonas aeruginosa and BambL from Burkholderia ambifaria. As a general trend, multivalency improved the binding to lectins and a higher affinity can be obtained by increasing to a certain limit the length of the spacer arm between the carbohydrate subunits and the central macrocyclic core.


Asunto(s)
Proteínas Bacterianas/química , Glicoconjugados/química , Lectinas/química , Pseudomonas aeruginosa/química , Compuestos de Amonio Cuaternario/síntesis química , Proteínas Bacterianas/metabolismo , Calixarenos , Lectinas/metabolismo , Modelos Moleculares , Unión Proteica , Compuestos de Amonio Cuaternario/química
17.
Chemistry ; 22(33): 11785-94, 2016 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-27412649

RESUMEN

Anti-infectious strategies against pathogen infections can be achieved through antiadhesive strategies by using multivalent ligands of bacterial virulence factors. LecA and LecB are lectins of Pseudomonas aeruginosa implicated in biofilm formation. A series of 27 LecA-targeting glycoclusters have been synthesized. Nine aromatic galactose aglycons were investigated with three different linker arms that connect the central mannopyranoside core. A low-nanomolar (Kd =19 nm, microarray) ligand with a tyrosine-based linker arm could be identified in a structure-activity relationship study. Molecular modeling of the glycoclusters bound to the lectin tetramer was also used to rationalize the binding properties observed.


Asunto(s)
Adhesinas Bacterianas/química , Galactosa/química , Lectinas/química , Pseudomonas aeruginosa/química , Adhesinas Bacterianas/metabolismo , Galactosa/metabolismo , Lectinas/metabolismo , Ligandos , Modelos Moleculares , Relación Estructura-Actividad
18.
Org Biomol Chem ; 14(13): 3476-81, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-26972051

RESUMEN

Anti-adhesive glycoclusters offer potential as therapeutic alternatives to classical antibiotics in treating infections. Pillar[5]arenes functionalised with either five galactose or five fucose residues were readily prepared using CuAAC reactions and evaluated for their binding to three therapeutically relevant bacterial lectins: LecA and Lec B from Pseudomonas aeuruginosa and BambL from Burkholderia ambifaria. Steric interactions were demonstrated to be a key factor in achieving good binding to LecA with more flexible galactose glycoclusters showing enhanced activity. In contrast binding to the fucose-selective lectins confirmed the importance of topology of the glycoclusters for activity with the pillar[5]arene ligand proving a selective ligand for BambL.


Asunto(s)
Burkholderia/química , Glicoconjugados/química , Lectinas/química , Pseudomonas aeruginosa/química , Compuestos de Amonio Cuaternario/química , Sitios de Unión , Calixarenos , Estructura Molecular
19.
Org Biomol Chem ; 13(46): 11244-54, 2015 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-26412676

RESUMEN

Pseudomonas aeruginosa (PA) and Burkholderia ambifaria (BA) are two opportunistic Gram negative bacteria and major infectious agents involved in lung infection of cystic fibrosis patients. Both bacteria can develop resistance to conventional antibiotherapies. An alternative strategy consists of targeting virulence factors in particular lectins with high affinity ligands such as multivalent glycoclusters. LecA (PA-IL) and LecB (PA-IIL) are two tetravalent lectins from PA that recognise galactose and fucose respectively. BambL lectin from BA is trimeric with 2 binding sites per monomer and is also specific for fucose. These three lectins are potential therapeutic targets in an anti-adhesive anti-bacterial approach. Herein, we report the synthesis of 18 oligonucleotide pentofuranose-centered or mannitol-centered glycoclusters leading to tri-, penta- or decavalent clusters with different topologies. The linker arm length between the core and the carbohydrate epitope was also varied leading to 9 galactoclusters targeting LecA and 9 fucoclusters targeting both LecB and BambL. Their dissociation constants (Kd) were determined using a DNA-based carbohydrate microarray technology. The trivalent xylo-centered galactocluster and the ribo-centered fucocluster exhibited the best affinity for LecA and LecB respectively while the mannitol-centered decafucocluster displayed the best affinity to BambL. These data demonstrated that the topology and nature of linkers were the predominant factors for achieving high affinity rather than valency.


Asunto(s)
Adhesinas Bacterianas/metabolismo , Burkholderia/metabolismo , Glicoconjugados/química , Glicoconjugados/farmacología , Lectinas/metabolismo , Pseudomonas aeruginosa/metabolismo , Sitios de Unión , Burkholderia/efectos de los fármacos , Infecciones por Burkholderia/tratamiento farmacológico , Infecciones por Burkholderia/microbiología , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Terapia Molecular Dirigida , Oligonucleótidos/química , Oligonucleótidos/farmacología , Unión Proteica , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos
20.
Org Biomol Chem ; 13(31): 8433-44, 2015 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-26090586

RESUMEN

Pseudomonas aeruginosa (PA) is a major public health care issue due to its ability to develop antibiotic resistance mainly through adhesion and biofilm formation. Therefore, targeting the bacterial molecular arsenal involved in its adhesion and the formation of its biofilm appears as a promising tool against this pathogen. The galactose-binding LecA (or PA-IL) has been described as one of the PA virulence factors involved in these processes. Herein, the affinity of three tetravalent mannose-centered galactoclusters toward LecA was evaluated with five different bioanalytical methods: HIA, ELLA, SPR, ITC and DNA-based glycoarray. Inhibitory potential towards biofilms was then assessed for the two glycoclusters with highest affinity towards LecA (Kd values of 157 and 194 nM from ITC measurements). An inhibition of biofilm formation of 40% was found for these galactoclusters at 10 µM concentration. Applications of these macromolecules in anti-bacterial therapy are therefore possible through an anti-adhesive strategy.


Asunto(s)
Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Galactosa/química , Galactosa/farmacología , Manosa/química , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Pruebas de Sensibilidad Microbiana
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