9 results on '"Esko, Jeffrey D."'
Search Results
2. Dendrimer-like PEO glycopolymers exhibit anti-inflammatory properties
- Author
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Rele, Shyam M., Tatton, Daniel, Wanxing Cui, Gnanou, Yves, Lianchun Wang, Esko, Jeffrey D., Sijan Hou, Chaikof, Elliot L., and Barr-Zarse, Ginger
- Subjects
Polysulfides -- Chemical properties ,Ethylene oxide -- Chemical properties ,Polymers -- Chemical properties ,Chemistry - Abstract
A new class of high molecular weight polysulfated poly (ethylene oxide) (PEO) dendrimer-like glycopolymer is synthesized by a combination of arm-first and core-first methodologies followed by trichloroacetimidate glycosidation as a facile bioconjunction strategy. The synthesis and biological evaluation of complex branched PEO heparinoid mimics, which provides an easily accessible route to carbohydrate-based compounds with anti-inflammatory activity in vivo is described.
- Published
- 2005
3. On Guanidinium and Cellular Uptake.
- Author
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Wexselblatt, Ezequiel, Esko, Jeffrey D., and Tor, Yitzhak
- Subjects
- *
GUANIDINES , *CHROMOSOMAL translocation , *CELL culture , *HYDROGEN bonding , *CELL membranes , *ORGANELLES - Abstract
Guanidinium-rich scaffolds facilitate cellular translocation and delivery of bioactive cargos through biological barriers. Although impressive uptake has been demonstrated for nonoligomeric and nonpept(o)idic guanidinylated scaffolds in cell cultures and animal models, the fundamental understanding of these processes is lacking. Charge pairing and hydrogen bonding with cell surface counterparts have been proposed, but their exact role remains putative. The impact of the number and spatial relationships of the guanidinium groups on delivery and organelle/organ localization is yet to be established. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
4. Differentiation of 3-O-Sulfated Heparin Disaccharide Isomers: Identification of Structural Aspects of the Heparin CCL2 Binding Motif
- Author
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Meissen, John K., Sweeney, Matthew D., Girardi, Matthew, Lawrence, Roger, Esko, Jeffrey D., and Leary, Julie A.
- Subjects
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HEPARIN , *GLUCOSAMINE , *DISACCHARIDES , *ANTITHROMBIN III , *TANDEM mass spectrometry , *DISSOCIATION (Chemistry) , *CHEMOKINES , *PROTEIN binding , *THERAPEUTICS - Abstract
The presence of 3-O-sulfated glucosamine residues in heparin or heparan sulfate plays a role in binding to antithrombin III and HSV infection. In this study, tandem mass spectrometry was used to differentiate between two heparin disaccharide isomers containing variable sulfate at C6 in a common disaccharide and C3 in a more rare one. The dissociation patterns shown by MS2 and MS3 were clearly distinguishable between the isomers, allowing their differentiation and quantitation. Using this technique, we show that an octasaccharide with 11 sulfate groups with high affinity for inflammatory chemokine CCL2 does not contain 3-O-sulfated disaccharides. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
5. Arylsulfatase K is the Lysosomal 2-Sulfoglucuronate Sulfatase.
- Author
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Dhamale OP, Lawrence R, Wiegmann EM, Shah BA, Al-Mafraji K, Lamanna WC, Lübke T, Dierks T, Boons GJ, and Esko JD
- Subjects
- Chromatography, Liquid, Glycosaminoglycans metabolism, Humans, Mass Spectrometry, Substrate Specificity, Arylsulfatases metabolism, Lysosomes enzymology
- Abstract
The degradation of glycosaminoglycans (GAGs) involves a series of exolytic glycosidases and sulfatases that act sequentially on the nonreducing end of the polysaccharide chain. Enzymes have been cloned that catalyze all of the known linkages with the exception of the removal of the 2-O-sulfate group from 2-sulfoglucuronate, which is found in heparan sulfate and dermatan sulfate. Here, we show using synthetic disaccharide substrates that arylsulfatase K is the glucuronate-2-sulfatase. Arylsulfatase K acts selectively on 2-sulfoglucuronate and lacks activity against 2-sulfoiduronate, whereas iduronate-2-sulfatase (IDS) desulfates synthetic disaccharides containing 2-sulfoiduronate but not 2-sulfoglucuronate. As arylsulfatase K has all of the properties expected of a lysosomal enzyme, we conclude that arylsulfatase K is the long sought lysosomal glucuronate-2-sulfatase, which we designate GDS.
- Published
- 2017
- Full Text
- View/download PDF
6. Expanding the 3-O-Sulfate Proteome--Enhanced Binding of Neuropilin-1 to 3-O-Sulfated Heparan Sulfate Modulates Its Activity.
- Author
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Thacker BE, Seamen E, Lawrence R, Parker MW, Xu Y, Liu J, Vander Kooi CW, and Esko JD
- Subjects
- Animals, Carbohydrate Sequence, Cattle, Humans, Mice, Oligosaccharides chemistry, Oligosaccharides metabolism, Heparitin Sulfate metabolism, Neuropilin-1 metabolism, Proteome, Sulfates metabolism
- Abstract
Binding of proteins to heparan sulfate is driven predominantly by electrostatic interactions between positively charged amino acid residues in the protein and negatively charged sulfate groups located at various positions along the polysaccharide chain. Although many heparin/heparan-sulfate-binding proteins have been described, few exhibit preferential binding for heparan sulfates containing relatively rare 3-O-sulfated glucosamine residues. To expand the "3-O-sulfate proteome," affinity matrices were created from Chinese hamster ovary (CHO) cell heparan sulfate engineered in vitro with and without 3-O-sulfate groups. Fractionation of different animal sera yielded several proteins that bound specifically to columns containing 3-O-sulfated heparan sulfate modified by two members of the heparan sulfate 3-O-sulfotransferase superfamily, Hs3st1 and Hs3st2. Neuropilin-1 was analyzed in detail because it has been implicated in angiogenesis and axon guidance. We show that 3-O-sulfation enhanced the binding of neuropilin-1 to heparan sulfate immobilized on plastic plates and to heparan sulfate present on cultured cells. Chemoenzymatically synthesized 3-O-sulfated heparan sulfate dodecamers protected neuropilin-1 from thermal denaturation and inhibited neuropilin-1-dependent, semaphorin-3a-induced growth cone collapse of neurons derived from murine dorsal root ganglia. The effect of 3-O-sulfation was cell autonomous and specific to Hs3st2 based on collapse assays of neurons derived from Hs3st1- and Hs3st2-deficient mice. Finally, 3-O-sulfated heparan sulfate enhanced the inhibition of endothelial cell sprouting by exogenous heparan sulfate. These findings demonstrate a reliable method to identify members of the 3-O-sulfate proteome and that 3-O-sulfation of heparan sulfate can modulate axonal growth cone collapse and endothelial cell sprouting.
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- 2016
- Full Text
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7. GNeosomes: Highly Lysosomotropic Nanoassemblies for Lysosomal Delivery.
- Author
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Wexselblatt E, Esko JD, and Tor Y
- Subjects
- Animals, Cell Line, Drug Liberation, Humans, Hydrophobic and Hydrophilic Interactions, Macromolecular Substances chemistry, Macromolecular Substances metabolism, Molecular Weight, Aminoglycosides chemistry, Drug Carriers chemistry, Lysosomes metabolism, Nanostructures chemistry
- Abstract
GNeosomes, lysosomotropic lipid vesicles decorated with guanidinoneomycin, can encapsulate and facilitate the cellular internalization and lysosomal delivery of cargo ranging from small molecules to high molecular weight proteins, in a process that is exclusively dependent on cell surface glycosaminoglycans. Their cellular uptake mechanism and co-localization with lysosomes, as well as the delivery, release, and activity of internalized cargo, are quantified. GNeosomes are proposed as a universal platform for lysosomal delivery with potential as a basic research tool and a therapeutic vehicle.
- Published
- 2015
- Full Text
- View/download PDF
8. Aggregation-mediated macromolecular uptake by a molecular transporter.
- Author
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Inoue M, Tong W, Esko JD, and Tor Y
- Subjects
- Animals, Binding Sites, Biological Transport, CHO Cells, Cricetinae, Cricetulus, Endocytosis, Heparan Sulfate Proteoglycans metabolism, Macromolecular Substances metabolism
- Abstract
Endocytosis is a key process in cellular delivery of macromolecules by molecular transporters, although the mechanism of internalization remains unclear. Here, we probe the cellular uptake of streptavidin using biotinylated guanidinoneomycin (biotinGNeo), a low molecular weight guanidinium-rich molecular transporter. Two distinct modes were explored: (i) incubation of cells with a preformed tetravalent streptavidin-(biotinGNeo)4 conjugate and (ii) preincubation of cells with the biotinGNeo before exposure to streptavidin. A significant enhancement in uptake was observed after preincubation with biotinGNeo. FRET studies showed that the enhanced uptake was accompanied by extensive aggregation of streptavidin on the cell surface. Because guanidinylated neomycin was previously found to exclusively bind to heparan sulfate, our observations suggest that heparan sulfate proteoglycan aggregation is a pivotal step for endocytic entry into cells by guanidinoglycosides. These observations put forward a practical and general pathway for the cellular delivery of diverse macromolecules.
- Published
- 2013
- Full Text
- View/download PDF
9. Stable RAGE-heparan sulfate complexes are essential for signal transduction.
- Author
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Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, and Esko JD
- Subjects
- Coordination Complexes metabolism, Dimerization, Drug Stability, Endothelial Cells enzymology, Heparitin Sulfate metabolism, Humans, Models, Molecular, Receptor for Advanced Glycation End Products metabolism, X-Ray Diffraction, Coordination Complexes chemistry, Heparitin Sulfate chemistry, Receptor for Advanced Glycation End Products chemistry, Signal Transduction
- Abstract
RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is believed to play an essential role in signal transduction, but the molecular mechanism of oligomerization remains elusive. Here we report that RAGE activation of Erk1/2 phosphorylation on endothelial cells in response to a number of ligands depends on a mechanism that involves heparan sulfate-induced hexamerization of the RAGE extracellular domain. Structural studies of the extracellular V-C1 domain-dodecasaccharide complex by X-ray diffraction and small-angle X-ray scattering revealed that the hexamer consists of a trimer of dimers, with a stoichiometry of 2:1 RAGE:dodecasaccharide. Mutagenesis studies mapped the heparan sulfate binding site and the interfacial surface between the monomers and demonstrated that electrostatic interactions with heparan sulfate and intermonomer hydrophobic interactions work in concert to stabilize the dimer. The importance of oligomerization was demonstrated by inhibition of signaling with a new epitope-defined monoclonal antibody that specifically targets oligomerization. These findings indicate that RAGE-heparan sulfate oligomeric complexes are essential for signaling and that interfering with RAGE oligomerization might be of therapeutic value.
- Published
- 2013
- Full Text
- View/download PDF
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