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1.
Eur J Pharm Biopharm ; 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32717389

RESUMO

Dynantin is a potent and selective synthetic polypeptide kappa opioid receptor antagonist which has potential antidepressant and anxiolytic-like therapeutic applications, however its clinical development has been hampered by plasma stability issues and poor penetration of the blood brain barrier. Targeted liposome delivery systems represent a promising and non-invasive approach to improving the delivery of therapeutic agents across the blood brain barrier. As part of our work focused on targeted drug delivery, we have developed a novel mannosylated liposome system. Herein, we investigate these glycoliposomes for the targeted delivery of dynantin to the central nervous system. Cholesterol was tested and optimized as a formulation excipient, where it improved particle stability as measured via particle size, entrapment and ex vivo plasma stability of dynantin. The in vitro PRESTO-tango assay system was used to confirm that glycoliposomal entrapment did not impact the affinity or activity of the peptide at its receptor. Finally, in vivo distribution studies in mice showed that the mannosylated glycoliposomes significantly improved delivery of dynantin to the brain. Overall, the results clearly demonstrate the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the central nervous system.

2.
Molecules ; 24(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581627

RESUMO

A set of three mannopyranoside possessing identical 1,1'-biphenyl glycosidic pharmacophore but different aglyconic atoms were synthesized using either a palladium-catalyzed Heck cross coupling reaction or a metathesis reaction between their corresponding allylic glycoside derivatives. Their X-ray structures, together with their calculated 3D structures, showed strong indicators to explain the observed relative binding abilities against E. coli FimH as measured by a improved surface plasmon resonance (SPR) method. Amongst the O-, C-, and S-linked analogs, the C-linked analog showed the best ability to become a lead candidate as antagonist against uropathogenic E. coli with a Kd of 11.45 nM.


Assuntos
Adesinas de Escherichia coli/metabolismo , Proteínas de Fímbrias/metabolismo , Hexoses/farmacologia , Escherichia coli Uropatogênica/fisiologia , Aderência Bacteriana/efeitos dos fármacos , Configuração de Carboidratos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Hexoses/síntese química , Hexoses/química , Modelos Moleculares , Ressonância de Plasmônio de Superfície , Escherichia coli Uropatogênica/efeitos dos fármacos
3.
Pathogens ; 8(3)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500262

RESUMO

Streptococcus suis serotype 2 is an encapsulated bacterium and an important swine pathogen. Opsonizing antibody responses targeting capsular polysaccharides (CPSs) are protective against extracellular pathogens. To elucidate the protective activity of monoclonal antibodies (mAbs) directed against S. suis serotype 2 CPS, mice were immunized with a serotype 2 CPS-glycoconjugate and three hybridomas were isolated; of which, two were murine IgMs and the other a murine IgG1. Whereas the IgMs (mAbs 9E7 and 13C8) showed different reactivity levels with S. suis serotypes 1, 1/2, 2 and 14, the IgG1 (mAb 16H11) was shown to be serotype 2-specific. All mAbs targeted the sialylated chain of the CPSs. Using an opsonophagocytosis assay, the IgMs were opsonizing towards the S. suis serotypes to which they cross-react, while the IgG1 failed to induce bacterial elimination. In a model of mouse passive immunization followed by a lethal challenge with S. suis serotype 2, the IgG1 and IgM cross-reacting only with serotype 14 (mAb 13C8) failed to protect, while the IgM cross-reacting with serotypes 1, 1/2, and 14 (mAb 9E7) was shown to be protective by limiting bacteremia. These new mAbs show promise as new S. suis diagnostic tools, as well as potential for therapeutic applications.

4.
Drug Discov Today ; 24(5): 1176-1183, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898662

RESUMO

Dendrimers are highly branched, star-shaped macromolecules with nanometer-scale dimensions that can be readily modified with a range of functional groups, thus modifying their physicochemical and biological properties. In nanomedicine, dendrimers can be used as vectors for the targeted delivery strategy of a variety of biologically active agents or can be used as drug per se. In the future, it will be necessary to designate and develop 'safe' dendrimers, which is currently a crucial concern. Here, we analyze the key in vitro physicochemical parameters to be considered for preclinical evaluation of biomedical dendrimers.


Assuntos
Dendrímeros/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/farmacologia , Hemólise/efeitos dos fármacos , Humanos , Estrutura Molecular , Nanomedicina
5.
Drug Discov Today ; 24(5): 1184-1192, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30904723

RESUMO

In nanomedicine, the widespread concern of nanoparticles in general, and dendrimers, in particular, is the analysis of key in-vivo physicochemical parameters to ensure the preclinical and clinical development of 'safe' bioactive nanomaterials. It is clear that for biomedical applications, biocompatible dendrimers, used as nanocarriers or active per se, should be devoid of toxicity and immunogenicity, and have adequate PK/PD behaviors (adequate exposure) in order to diffuse in different tissues. Functionalization of dendrimers has a dramatic effect on in-vivo physicochemical parameters. In this review, we highlighted key in-vivo physicochemical properties, based on data from biochemical, cellular and animal models, to provide biocompatible dendrimers. Up-to-date, only scarce studies have been described on this topic.


Assuntos
Dendrímeros , Animais , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Dendrímeros/toxicidade , Humanos , Polímeros/química , Polímeros/farmacocinética , Polímeros/farmacologia , Polímeros/toxicidade
6.
J Hazard Mater ; 364: 356-366, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30384246

RESUMO

Catalytic ozonation of Methylene Blue, Methyl Green, Methyl Orange and Methyl-thymol Blue was investigated in the presence of ion-exchanged montmorillonite (NaMt and Fe(II)Mt), crude bentonite and acid-activated counterparts. An original approach never tackled so far consisted in correlating the basicity and hydrophilic character to the dye-catalyst interactions occurring on the catalyst surface. This was achieved through CO2 and water thermal programmed desorption. Kinetics study revealed that ozonation starts in the bulk solution, and dye adsorption turns out to be an essential requirement for high catalytic effectiveness. On NaMt, dye molecules appear to adsorb mainly via hydrophobic interaction. On Fe(II)Mt, the contributions of hydrophobic interaction, cation-exchange and Fe2+ mobility to the catalytic activity prevail. Acid activated clay catalysts exhibited lowest hydrophilic character favoring adsorption through organophilic interaction and affording thorough and fast dye mineralization. This was explained in terms of increased number of silanols and -Si-O-Si- groups. For all catalysts, short ozonation of all dye molecules resulted in similar end-chain products, which were totally eliminated after prolonged reaction times. This result is of great importance because it provides valuable theoretical findings that allow envisaging total mineralization of organic molecules by recyclable metal-free clay catalysts.

7.
Acc Chem Res ; 51(11): 2937-2948, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30289687

RESUMO

Preventing bacterial adhesion to host cells is a provocative and alternative approach to traditional antibiotic treatments given the increasing microbial resistance. A brief overview of common antibiotic treatments is described in light of their respective resistance and remaining susceptibility. This strategy has been seriously considered in the context of adherent-invasive infections in Crohn's disease and urinary tract infections in particular. The adhesions of various pathogenic Escherichia coli strains to host cells are primarily mediated through carbohydrate-protein interactions involving bacterial organelles called fimbriae that can recognize specific glycoconjugate receptors on host cells. Of particular interest are the FimH and PapG fimbriae, which bind to mannosylated glycoproteins and glycolipids of the galabiose series, respectively. Therefore, blocking FimH- and PapG-mediated bacterial adhesion to uroepithelial cells by high-affinity carbohydrate antagonists constitutes a challenging therapeutic target of high interest. This is of particular interest since bacterial adhesion to host cells is a parameter unlikely to be the subject of bacterial mutations without affecting the carbohydrate ligand binding interactions at the basis of the recognition and infection processes. To date, there have been several families of potent FimH antagonists that include natural O-linked as well as unnatural analogues of α-d-mannopyranosides. These observations led to a thorough understanding of the intimate binding site interactions that helped to reveal the so-called "tyrosine gate mechanism" at the origin of the strong necessary interactions with sugar-possessing hydrophobic aglycones. By modification of the aglycones of single monosaccharidic d-mannopyranosides, it was possible to replace the natural complex oligomannoside structure by simpler ones. An appealing and successful series of analogues have been disclosed, including nanomolecular architectures such as dendrimers, polymers, and liposomes. In addition, the data were compared to the above multivalent architectures and confirmed the possibility of working with small sugar candidates. This Account primarily concentrates on the most promising types of FimH inhibitors belonging to the family of α-C-linked mannopyranosides. However, one of the drawbacks associated with C-mannopyranosides has been that they were believed to be in the inverted chair conformation, which is obviously not recognized by the E. coli FimH. To decipher this situation, various synthetic approaches, conformational aspects, and restrictions are discussed using molecular modeling, high-field NMR spectroscopy, and X-ray analysis. These combined techniques pointed to the fact that several α-C-linked mannopyranosides do exist in the required 4C1 chair conformation. Ultimately, recent findings in this growing field of interest culminated in the identification of drug candidates that have reached clinical phase I.


Assuntos
Infecções por Escherichia coli/terapia , Manosídeos/química , Adesinas de Escherichia coli/metabolismo , Animais , Antibacterianos , Antígenos CD , Aderência Bacteriana/efeitos dos fármacos , Moléculas de Adesão Celular , Farmacorresistência Bacteriana , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Proteínas de Fímbrias/antagonistas & inibidores , Proteínas de Fímbrias/metabolismo , Fímbrias Bacterianas/metabolismo , Proteínas Ligadas por GPI , Humanos , Manosídeos/farmacologia , Manosídeos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/patologia
8.
PLoS One ; 13(9): e0204071, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30235253

RESUMO

Obesity is increasingly prevalent and associated with increased risk of developing type 2 diabetes, cardiovascular diseases, and cancer. Magnetic resonance imaging (MRI) is an accurate method for determination of body fat volume and distribution. However, quantifying body fat from numerous MRI slices is tedious and time-consuming. Here we developed a deep learning-based method for measuring visceral and subcutaneous fat in the abdominal region of mice. Congenic mice only differ from C57BL/6 (B6) Apoe knockout (Apoe-/-) mice in chromosome 9 that is replaced by C3H/HeJ genome. Male congenic mice had lighter body weight than B6-Apoe-/- mice after being fed 14 weeks of Western diet. Axial and coronal T1-weighted sequencing at 1-mm-thickness and 1-mm-gap was acquired with a 7T Bruker ClinScan scanner. A deep learning approach was developed for segmenting visceral and subcutaneous fat based on the U-net architecture made publicly available through the open-source ANTsRNet library-a growing repository of well-known neural networks. The volumes of subcutaneous and visceral fat measured through our approach were highly comparable with those from manual measurements. The Dice score, root-mean-square error (RMSE), and correlation analysis demonstrated the similarity between two methods in quantifying visceral and subcutaneous fat. Analysis with the automated method showed significant reductions in volumes of visceral and subcutaneous fat but not non-fat tissues in congenic mice compared to B6 mice. These results demonstrate the accuracy of deep learning in quantification of abdominal fat and its significance in determining body weight.


Assuntos
Gordura Abdominal/anatomia & histologia , Aprendizado Profundo , Imagem por Ressonância Magnética , Tecido Adiposo/anatomia & histologia , Animais , Apolipoproteínas E/deficiência , Automação , Peso Corporal , Dieta Ocidental , Feminino , Gordura Intra-Abdominal/anatomia & histologia , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos , Fenótipo , Gordura Subcutânea/anatomia & histologia
9.
PLoS One ; 13(9): e0204472, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30260999

RESUMO

The therapeutic application of peptide-based drugs is significantly limited by the rapid proteolytic degradation that occurs when in blood. Encapsulation of these peptide structures within a delivery system, such as liposomes, can greatly improve both stability and target delivery. As part of our work focused on novel ambiphilic mannosylated neoglycolipids as targeted drug delivery systems, we have developed a C14-alkyl-mannopyranoside that forms self-assembled monodisperse liposomes. Herein, these glycoliposomes are investigated as a potential method to improve the plasma stability of peptide-based drugs. Reversed phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) methods were developed to assess the in vitro plasma stability of two structurally diverse peptides, including the kappa opioid receptor selective antagonist dynantin, and the NOD2 innate immune receptor ligand muramyl dipeptide (MDP). The RP-HPLC methods developed were able to resolve the peptides from background plasma contaminants and provided suitable response levels and linearity over an appropriate concentration range. Both compounds were found to be significantly degraded in rat plasma. Increasing degrees of both entrapment and stabilization were noted when dynantin was combined with the C14-alkyl-mannopyranoside in increasing peptide:glycoside ratios. The combination of MDP with the glycolipid also led to peptide entrapment, which greatly improved the plasma stability of the peptide. Overall, the results clearly indicate that the stability of peptide-based structures, which are subject to degradation in plasma, can be greatly improved via entrapment within C14-alkyl-mannopyranoside-bearing glycoliposomes.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Estabilidade de Medicamentos , Dinorfinas/administração & dosagem , Dinorfinas/sangue , Dinorfinas/farmacocinética , Feminino , Glicolipídeos/administração & dosagem , Glicolipídeos/química , Técnicas In Vitro , Lipossomos/administração & dosagem , Lipossomos/química , Nanopartículas/química , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/sangue , Antagonistas de Entorpecentes/farmacocinética , Peptídeos/sangue , Estabilidade Proteica , Proteólise , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/antagonistas & inibidores , Espectrometria de Massas por Ionização por Electrospray
10.
Molecules ; 23(8)2018 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-30060568

RESUMO

An efficient study of carbohydrate-protein interactions was achieved using multivalent glycodendrimer library. Different dendrimers with varied peripheral sugar densities and linkers provided an arsenal of potential novel therapeutic agents that could be useful for better specific action and greater binding affinities against their cognate protein receptors. Highly effective click chemistry represents the basic method used for the synthesis of mannosylated dendrimers. To this end, we used propargylated scaffolds of varying sugar densities ranging from 2 to 18 for the attachment of azido mannopyranoside derivatives using copper catalyzed click cycloaddition. Mannopyranosides with short and pegylated aglycones were used to evaluate their effects on the kinetics of binding. The mannosylated dendrons were built using varied scaffolds toward the accelerated and combined "onion peel" strategy These carbohydrates have been designed to fight E. coli urinary infections, by inhibiting the formation of bacterial biofilms, thus neutralizing the adhesion of FimH type 1 lectin present at the tip of their fimbriae against the natural multiantennary oligomannosides of uroplakin 1a receptors expressed on uroepithelial tissues. Preliminary DLS studies of the mannosylated dendrimers to cross- link the leguminous lectin Con A used as a model showed their high potency as candidates to fight the E. coli adhesion and biofilm formation.


Assuntos
Antibacterianos/síntese química , Biofilmes/efeitos dos fármacos , Dendrímeros/síntese química , Lectinas/química , Manose/química , Oligossacarídeos/química , Adesinas de Escherichia coli/genética , Adesinas de Escherichia coli/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Azidas/química , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Química Click , Concanavalina A/química , Concanavalina A/metabolismo , Reação de Cicloadição , Dendrímeros/metabolismo , Dendrímeros/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Proteínas de Fímbrias/genética , Proteínas de Fímbrias/metabolismo , Fímbrias Bacterianas/química , Fímbrias Bacterianas/efeitos dos fármacos , Fímbrias Bacterianas/metabolismo , Expressão Gênica , Glicosilação , Humanos , Lectinas/metabolismo , Modelos Biológicos , Polietilenoglicóis/química , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Uroplaquina Ia/genética , Uroplaquina Ia/metabolismo , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Urotélio/microbiologia
11.
Rapid Commun Mass Spectrom ; 32(17): 1573-1582, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29920820

RESUMO

RATIONALE: Acetaminophen (APAP) is a well-known analgesic, deemed a very safe over-the-counter medication. However, it is also the main cause of acute liver failure (ALF) in the Western world, via the formation of its reactive metabolite, N-acetyl p-benzoquinone imine (NAPQI), and its covalent attachment to liver proteins. The aim of this study was to develop a sensitive and robust quantitative assay to monitor APAP-protein binding to human serum albumin (HSA) in patient samples. METHODS: A combination of isotope dilution, peptic digestion and solid-phase extraction coupled to liquid chromatography/multiple reaction monitoring (LC/MRM) was employed. An external calibration curve with surrogate modified protein spiked into blank serum was used for absolute quantitation. Samples were analyzed by LC/MRM to measure the modified active site peptide of HSA. The LC/MRM assay was validated and successfully applied to serum samples from patients suffering from APAP-induced ALF. RESULTS: Accuracy ranged from 83.8-113.3%, within-run coefficient of variation (CV) ranged from 0.3-6.9%, and total CVs from 1.6-10.6%. Patient samples ranged from 0.12-3.91 nmol/mL NAPQI-HSA; in-between the assay dynamic range of 0.11-50.13 nmol/mL serum. In vivo median concentrations were found to be 0.62 nmol/mL and 0.91 nmol/mL for non-spontaneous survivors (n = 25) and individuals with irreversible liver damage (n = 10), respectively (p-value = 0.028), demonstrating significant potential as a biomarker for ALF outcome. CONCLUSIONS: A fast and sensitive assay was developed to accurately quantify NAPQI-HSA as a biomarker for APAP-related covalent binding in human serum.


Assuntos
Acetaminofen/efeitos adversos , Cromatografia Líquida/métodos , Falência Hepática Aguda/sangue , Albumina Sérica Humana/análise , Espectrometria de Massas em Tandem/métodos , Acetaminofen/administração & dosagem , Adulto , Estudos de Coortes , Feminino , Humanos , Falência Hepática Aguda/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Albumina Sérica Humana/metabolismo
12.
Transl Oncol ; 11(2): 450-466, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29477636

RESUMO

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need.

13.
Biochimie ; 146: 127-138, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29248541

RESUMO

Despite its natural abundance in lenses of vertebrates the physiological function(s) of the galectin-related inter-fiber protein (GRIFIN) is (are) still unclear. The same holds true for the significance of the unique interspecies (fish/birds vs mammals) variability in the capacity to bind lactose. In solution, ultracentrifugation and small angle X-ray scattering (at concentrations up to 9 mg/mL) characterize the protein as compact and stable homodimer without evidence for aggregation. The crystal structure of chicken (C-)GRIFIN at seven pH values from 4.2 to 8.5 is reported, revealing compelling stability. Binding of lactose despite the Arg71Val deviation from the sequence signature of galectins matched the otherwise canonical contact pattern with thermodynamics of an enthalpically driven process. Upon lactose accommodation, the side chain of Arg50 is shifted for hydrogen bonding to the 3-hydroxyl of glucose. No evidence for a further ligand-dependent structural alteration was obtained in solution by measuring hydrogen/deuterium exchange mass spectrometrically in peptic fingerprints. The introduction of the Asn48Lys mutation, characteristic for mammalian GRIFINs that have lost lectin activity, lets labeled C-GRIFIN maintain capacity to stain tissue sections. Binding is no longer inhibitable by lactose, as seen for the wild-type protein. These results establish the basis for detailed structure-activity considerations and are a step to complete the structural description of all seven members of the galectin network in chicken.


Assuntos
Galectinas/química , Animais , Sítios de Ligação , Metabolismo dos Carboidratos , Galinhas , Cristalografia por Raios X , Galectinas/metabolismo , Modelos Moleculares , Estrutura Quaternária de Proteína , Soluções
14.
Adv Drug Deliv Rev ; 136-137: 73-81, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29155170

RESUMO

Nanomedicine, which is an application of nanotechnologies in healthcare is developed to improve the treatments and lives of patients suffering from a range of disorders and to increase the successes of drug candidates. Within the nanotechnology universe, the remarkable unique and tunable properties of dendrimers have made them promising tools for diverse biomedical applications such as drug delivery, gene therapy and diagnostic. Up-to-date, very few dendrimers has yet gained regulatory approval for systemic administration, why? In this critical review, we briefly focus on the list of desired basic dendrimer requirements for decision-making purpose by the scientists (go/no-go decision), in early development stages, to become clinical candidates, and to move towards Investigational New Drugs (IND) application submission. In addition, the successful translation between research and clinic should be performed by the implementation of a simple roadmap to jump the 'valley of death' successfully.


Assuntos
Dendrímeros , Drogas em Investigação , Nanomedicina , Tomada de Decisões , Dendrímeros/administração & dosagem , Drogas em Investigação/administração & dosagem , Humanos
15.
Phys Chem Chem Phys ; 19(43): 29333-29343, 2017 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-29075707

RESUMO

Copper-loaded organo-montmorillonite showed improved affinity towards hydrogen under ambient conditions. Clay ion exchange with a propargyl-ended cation followed by thiol-yne coupling with thioglycerol resulted in a porous structure with a 6 fold higher specific surface area, which dramatically decreased after copper incorporation. X-ray diffraction and photoelectron spectrometry, nuclear magnetic resonance (1H and 13C) and CO2-thermal programmed desorption revealed strong sulfur:Cu0 and oxygen:Cu0 interactions. This was explained in terms of structure compaction that 'traps' Cu0 nanoparticles (CuNPs) and reduces their mobility. Transmission electron microscopy showed predominant 1.0-1.5 nm CuNPs. Hydrogen capture appears to involve predominantly physical interaction, since differential scanning calorimetry measurements gave low desorption heat and almost complete gas release between 20 °C and 75 °C. Possible hydrogen condensation within the compacted structure should hinder gas diffusion inside CuNPs and prevent chemisorption. These results allow safe hydrogen storage with easy gas release to be envisaged even at room temperature under vacuum. The reversible capture of hydrogen can be even more attractive when using natural inorganic supports and commercial plant-derived dendrimers judiciously functionalized, even at the expense of porosity.

16.
Chem Rev ; 117(15): 9839-9873, 2017 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-28682060

RESUMO

Among other classes of biomolecules, carbohydrates and glycoconjugates are widely involved in numerous biological functions. In addition to addressing the related synthetic challenges, glycochemists have invested intense efforts in providing access to structures that can be used to study, activate, or inhibit these biological processes. Over the past few decades, aminooxylated carbohydrates have been found to be key building blocks for achieving these goals. This review provides the first in-depth overview covering several aspects related to the syntheses and applications of aminooxylated carbohydrates. After a brief introduction to oxime bonds and their relative stabilities compared to related C═N functions, synthetic aspects of oxime ligation and methodologies for introducing the aminooxy functionality onto both glycofuranosyls and glycopyranosyls are described. The subsequent section focuses on biological applications involving aminooxylated carbohydrates as components for the construcion of diverse architectures. Mimetics of natural structures represent useful tools for better understanding the features that drive carbohydrate-receptor interaction, their biological output and they also represent interesting structures with improved stability and tunable properties. In the next section, multivalent structures such as glycoclusters and glycodendrimers obtained through oxime ligation are described in terms of synthetic design and their biological applications such as immunomodulators. The second-to-last section discusses miscellaneous applications of oxime-based glycoconjugates, such as enantioselective catalysis and glycosylated oligonucleotides, and conclusions and perspectives are provided in the last section.


Assuntos
Carboidratos/química , Carboidratos/síntese química , Glicoproteínas/química , Oligonucleotídeos/química , Estereoisomerismo
17.
Molecules ; 22(7)2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28671638

RESUMO

Antagonists of the Escherichia coli type-1 fimbrial adhesin FimH are recognized as attractive alternatives for antibiotic therapies and prophylaxes against acute and recurrent bacterial infections. In this study α-d-mannopyranosides O- or C-linked with an alkyl, alkene, alkyne, thioalkyl, amide, or sulfonamide were investigated to fit a hydrophobic substituent with up to two aryl groups within the tyrosine gate emerging from the mannose-binding pocket of FimH. The results were summarized into a set of structure-activity relationships to be used in FimH-targeted inhibitor design: alkene linkers gave an improved affinity and inhibitory potential, because of their relative flexibility combined with a favourable interaction with isoleucine-52 located in the middle of the tyrosine gate. Of particular interest is a C-linked mannoside, alkene-linked to an ortho-substituted biphenyl that has an affinity similar to its O-mannosidic analog but superior to its para-substituted analog. Docking of its high-resolution NMR solution structure to the FimH adhesin indicated that its ultimate, ortho-placed phenyl ring is able to interact with isoleucine-13, located in the clamp loop that undergoes conformational changes under shear force exerted on the bacteria. Molecular dynamics simulations confirmed that a subpopulation of the C-mannoside conformers is able to interact in this secondary binding site of FimH.


Assuntos
Adesinas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Proteínas de Fímbrias/metabolismo , Manosídeos/farmacologia , Adesinas de Escherichia coli/química , Aderência Bacteriana , Sítios de Ligação , Escherichia coli/efeitos dos fármacos , Proteínas de Fímbrias/química , Manosídeos/química , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
18.
Histochem Cell Biol ; 147(2): 285-301, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28013366

RESUMO

A hallmark of endogenous lectins is their ability to select a few distinct glycoconjugates as counterreceptors for functional pairing from the natural abundance of cellular glycoproteins and glycolipids. As a consequence, assays to assess inhibition of lectin binding should necessarily come as close as possible to the physiological situation, to characterize an impact of a synthetic compound on biorelevant binding with pharmaceutical perspective. We here introduce in a proof-of-principle manner work with sections of paraffin-embedded tissue (jejunum, epididymis) and labeled adhesion/growth-regulatory galectins, harboring one (galectin-1 and galectin-3) or two (galectin-8) types of lectin domain. Six pairs of synthetic lactosides from tailoring of the headgroup (3'-O-sulfation) and the aglycone (ß-methyl to aromatic S- and O-linked extensions) as well as three bi- to tetravalent glycoclusters were used as test compounds. Varying extents of reduction in staining intensity by synthetic compounds relative to unsubstituted/free lactose proved the applicability and sensitivity of the method. Flanking cytofluorimetric assays on lectin binding to native cells gave similar grading, excluding a major impact of tissue fixation. The experiments revealed cell/tissue binding of galectin-8 preferentially via one domain, depending on the cell type so that the effect of an inhibitor in a certain context cannot be extrapolated to other cells/tissues. Moreover, the work with the other galectins attests that this assay enables comprehensive analysis of the galectin network in serial tissue sections to determine overlaps and regional differences in inhibitory profiles.


Assuntos
Galectinas/química , Galectinas/metabolismo , Citometria de Fluxo , Galectinas/classificação , Glicosídeos/síntese química , Glicosídeos/química , Glicosídeos/metabolismo , Humanos , Lectinas/química , Lectinas/metabolismo , Ligação Proteica
19.
Chemosphere ; 168: 1648-1657, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27939664

RESUMO

Hematite-SBA-16 mixture (HS) exhibited high catalytic activity in Orange-G (OG) ozonation in water. Total OG discoloration was achieved in half the time required with hematite or SBA-16 alone, all UV-Vis bands disappeared in less than 2 min. Liquid chromatography- Mass spectrometry (LC-MS) revealed that OG ozonation triggers via both hydroxylation and desulfonation of the aromatic rings into specific intermediates. Prolonged ozonation in the presence of hematite and SBA-16 alone resulted in different distributions of common derivatives. The latter were not detected after 25 min ozonation with HS. Stochastic modeling of the evolution in time of the UV-Vis bands of OG revealed strong binary interaction between the initial pH and catalyst concentration. This was explained in terms of reciprocal contributions of: i. the catalytic properties of hematite in spite of its low porosity; ii. the high specific surface area of SBA-16 for adsorption and surface reaction notwithstanding its low intrinsic catalytic activity. The weak basicity of SBA-16 surface seems to play a key-role in adsorption. These findings are of great interest for envisaging flexible oxidative treatments, where Fe3+ containing soils or mixtures of sand and rust may also act as catalyst for total mineralization of various azo-dyes, regardless to their structures.


Assuntos
Compostos Azo/química , Corantes/química , Compostos Férricos/química , Ozônio/química , Dióxido de Silício/química , Adsorção , Catálise , Oxirredução , Poluentes Químicos da Água/química
20.
Molecules ; 21(5)2016 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-27187342

RESUMO

Glycan recognition by sugar receptors (lectins) is intimately involved in many aspects of cell physiology. However, the factors explaining the exquisite selectivity of their functional pairing are not yet fully understood. Studies toward this aim will also help appraise the potential for lectin-directed drug design. With the network of adhesion/growth-regulatory galectins as therapeutic targets, the strategy to recruit synthetic chemistry to systematically elucidate structure-activity relationships is outlined, from monovalent compounds to glyco-clusters and glycodendrimers to biomimetic surfaces. The versatility of the synthetic procedures enables to take examining structural and spatial parameters, alone and in combination, to its limits, for example with the aim to produce inhibitors for distinct galectin(s) that exhibit minimal reactivity to other members of this group. Shaping spatial architectures similar to glycoconjugate aggregates, microdomains or vesicles provides attractive tools to disclose the often still hidden significance of nanometric aspects of the different modes of lectin design (sequence divergence at the lectin site, differences of spatial type of lectin-site presentation). Of note, testing the effectors alone or in combination simulating (patho)physiological conditions, is sure to bring about new insights into the cooperation between lectins and the regulation of their activity.


Assuntos
Carboidratos/química , Galectinas/química , Glicoproteínas/química , Polissacarídeos/química , Dendrímeros/química , Galectinas/metabolismo , Glicoproteínas/síntese química , Humanos , Modelos Moleculares , Polissacarídeos/metabolismo , Relação Estrutura-Atividade
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