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1.
Blood ; 138(13): 1182-1193, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33945603

RESUMO

Events mediated by the P-selectin/PSGL-1 pathway play a critical role in the initiation and propagation of venous thrombosis by facilitating the accumulation of leukocytes and platelets within the growing thrombus. Activated platelets and endothelium express P-selectin, which binds P-selectin glycoprotein ligand-1 (PSGL-1) that is expressed on the surface of all leukocytes. We developed a pegylated glycomimetic of the N terminus of PSGL-1, PEG40-GSnP-6 (P-G6), which proved to be a highly potent P-selectin inhibitor with a favorable pharmacokinetic profile for clinical translation. P-G6 inhibits human and mouse platelet-monocyte and platelet-neutrophil aggregation in vitro and blocks microcirculatory platelet-leukocyte interactions in vivo. Administration of P-G6 reduces thrombus formation in a nonocclusive model of deep vein thrombosis with a commensurate reduction in leukocyte accumulation, but without disruption of hemostasis. P-G6 potently inhibits the P-selectin/PSGL-1 pathway and represents a promising drug candidate for the prevention of venous thrombosis without increased bleeding risk.

2.
Chem Sci ; 11(48): 13052-13059, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34123241

RESUMO

An anticancer, entirely carbohydrate conjugate, Globo H-polysaccharide A1 (Globo H-PS A1), was chemically prepared and immunologically evaluated in C57BL/6 mice. Tumor associated carbohydrate antigen Globo H hexasaccharide was synthesized in an overall 7.8% yield employing a convergent [3 + 3] strategy that revealed an anomeric aminooxy group used for conjugation to oxidized PS A1 via an oxime linkage. Globo H-PS A1, formulated with adjuvants monophosphoryl lipid A and TiterMax® Gold. After immunization an antigen specific immune response was observed in ELISA with anti-Globo H IgG/IgM antibodies. Specificity of the corresponding antibodies was determined by FACS showing cell surface binding to Globo H-positive cancer cell lines MCF-7 and OVCAR-5. The anti-Globo H antibodies also exhibited complement-dependent cellular cytotoxicity against MCF-7 and OVCAR-5 cells.

3.
Org Lett ; 20(15): 4526-4530, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30015493

RESUMO

The tetrasaccharide repeating unit of zwitterionic polysaccharide A1 (PS A1) from Bacteroides fragilis ATCC 25285/NCTC 9343 has been synthesized using a linear glycosylation approach. One key step includes an α(1,4)-stereoselective [2 + 1] glycosylation of a 2,4,6-trideoxy-2-acetamido-4-amino-d-Gal p (AAT) donor with a poorly reactive axial C4-OH disaccharide acceptor. Mild acid-mediated deacetylation and a challenging [3 + 1] glycosylation are also highlighted. The strategy is inclusive of a single-pot, three-step deprotection affording PS A1 with alternating charges on adjacent monosaccharide units.


Assuntos
Bacteroides fragilis/química , Monossacarídeos/química , Oligossacarídeos/química , Polissacarídeos Bacterianos/química , Polissacarídeos/síntese química , Sequência de Carboidratos , Catálise , Galactose/química , Glicosilação , Metais/química
4.
Acta Crystallogr D Biol Crystallogr ; 70(Pt 2): 451-60, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24531479

RESUMO

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 Šresolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Proteínas Adaptadoras de Transporte Vesicular/química , Cumarínicos/química , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequenas/química , Proteínas Adaptadoras de Transporte Vesicular/genética , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Células HEK293 , Humanos , Leucina/química , Ligantes , Neurotensina/química , Fenilalanina/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 24(1): 177-80, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24355129

RESUMO

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Hidrocarbonetos Fluorados/farmacologia , Piridinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade
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