Sialyl Lewis x Liposomes as a Multivalent Ligand and Inhibitor of E-Selectin Mediated Cellular Adhesion

DeFrees, Shawn; Phillips, Lauren; Guo, Lin; Zalipsky, Samuel

doi:10.1021/ja954122g

Cited by 113 publications

(71 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Carbohydrate-protein binding events usually involve several simultaneous contacts between carbohydrates that are clustered on cell surfaces and protein receptors that contain multiple carbohydrate-binding sites. Numerous studies on model systems have demonstrated that polyvalent displays of carbohydrates can lead to remarkably high binding avidities (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Because avidity and specificity are not necessarily correlated (6,7), however, polyvalency does not completely resolve the paradox of how marginally selective carbohydrate-binding interactions can produce highly specific responses.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Nonstatistical binding of a protein to clustered carbohydrates

Horan

Yan

Isobe

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

198

163

View full text Add to dashboard Cite

Carbohydrate-derivatized self-assembled monolayers (SAMs) are used as a model system to address issues involving cell-surface carbohydrate-protein interactions. Here we examine the influence of carbohydrate surface density on protein-binding avidity. We show that the binding selectivity of Bauhinia purpurea lectin switches from one carbohydrate ligand to another as the surface density of the carbohydrate ligands increases from values of sugar Ϸ 0.1-1.0. Polyvalent binding is possible at all surface densities investigated; hence, the switch in selectivity is not due simply to the achievement of a critical density that permits polyvalent contacts. Instead, secondary interactions at high surface densities promote a switch in carbohydrate-binding selectivity. These findings may have implications for how changes in the composition and the density of cell-surface carbohydrates influence biological recognition processes and regulatory pathways. The patterns of expression of cell-surface carbohydrates change during development and differentiation (1-3). Changes in the composition of cell-surface carbohydrates also occur during oncogenesis and metastasis (4, 5). Although the biological functions of cell-surface carbohydrates are still incompletely defined, it is believed that they are somehow involved in signaling pathways that determine the temporal and spatial identity of cells. How changing patterns of cell-surface carbohydrates are linked to cell growth and differentiation is not understood.The early steps in cell-surface carbohydrate-mediated cellular processes are presumed to involve binding events between carbohydrates and receptors in the plasma or on the surface of other cells. Because these binding events are linked to specific cellular responses, one might expect them to be highly specific. However, studies in solution have shown that carbohydrateprotein binding interactions have dissociation constants that are typically in the mM range and that different carbohydrate ligands have similar affinities for the same protein receptor. If carbohydrates bind weakly and with poor selectivity, how can they mediate specific cellular processes?This paradox has been partially explained by the phenomenon of polyvalency. Carbohydrate-protein binding events usually involve several simultaneous contacts between carbohydrates that are clustered on cell surfaces and protein receptors that contain multiple carbohydrate-binding sites. Numerous studies on model systems have demonstrated that polyvalent displays of carbohydrates can lead to remarkably high binding avidities (6-16). Because avidity and specificity are not necessarily correlated (6, 7), however, polyvalency does not completely resolve the paradox of how marginally selective carbohydrate-binding interactions can produce highly specific responses.Two mechanisms have been proposed to explain how specificity can be achieved in cell-surface carbohydrate-binding interactions. In one mechanism, polyvalent carbohydrate-protein interactions facilitate the adhesion of cells. T...

show abstract

mentioning

confidence: 99%

“…Simplified model systems are usually used to study polyvalent carbohydrate-protein interactions (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). We recently demonstrated that carbohydrates presented on TentaGel beads exhibit polyvalent binding and may therefore be useful as model systems to investigate the interactions of carbohydrates on surfaces (6, 7).…”

mentioning

confidence: 99%

Nonstatistical binding of a protein to clustered carbohydrates

Horan

Yan

Isobe

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

198

163

View full text Add to dashboard Cite

show abstract

“…In the natural form, Lewis antigens are attached through their reducing ends to lipids and/or proteins. If Lewis antigen conjugates have the lipids attached to the 2-amino group of the glucosamine residue with the reducing end capped by an unreactive group [38], it may affect the conformation of the antigen and their binding to selectins. Therefore, SuLe a -containing glycolipids 1a and 1b with the lipid moiety at the saccharide reducing end have the advantage of stability under physiological conditions.…”

Section: Synthesis Of Sule a -And Tsule A -Lipidsmentioning

confidence: 99%

“…They bind E-, P-and L-selectin receptors present on activated endothelial cells, platelets and leukocytes during the inflammation process [33][34][35][36]. Therefore, much effort has been focused on the development of new therapeutic strategies for inflamatory diseases, based on using SLe x/a ligands and their analogs [37][38][39][40]. To explore this approach, we have synthesized a natural Lewis type saccharide ligand, 3'-sulfoLewis a (SuLe a ), as well as its glycolipids, and incorporated them into liposomes for targeting P-selectin expressed on activated platelets [41][42].…”

Section: Introductionmentioning

confidence: 99%

Vesicle size and stability of biomimetic liposomes from 3′-sulfo-Lewis a (SuLea) containing glycolipids

Zhu

Xue

Guo

et al. 2007

Colloids and Surfaces B: Biointerfaces

View full text Add to dashboard Cite

We report on the use of a natural Lewis type saccharide ligand, 3'-sulfo-Lewis a (SuLe a ) for glycocalyx-mimetic surface modification of liposomes. Two SuLe a -containing glycolipids, monovalent SuLe a -lipid and trivalent SuLe a (TSuLe a )-lipid, were synthesized, and used with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol to prepare unilaminar vesicles (ULVs) by a freeze-thaw and extrusion method. The effects of the glycolipid concentrations and the pore sizes of extrusion membranes on vesicle size and stability were investigated by photon correlation spectroscopy (PCS). Glycoliposomes, with 5% SuLe a -or TSuLe a -lipids obtained by 50 nm extrusion, had 25-30% more vesicles less than 100 nm in diameter compared with the 100 nm extrusion. TSuLe a -liposomes always produced larger vesicle size than SuLe a -liposomes, which we attribute to the larger TSuLe a headgroup. Both SuLe a -and TSuLe a -liposomes increased their vesicle size with increasing glycolipid concentration from 5% to 15%, and demonstrated good stability at room temperature for over one month. Further increasing the glycolipid concentration to 20% resulted in large vesicle aggregation after 5 days for TSuLe a -liposomes, while the SuLe a -liposomes remained stable for 10 days. SuLe a -and TSuLe a -liposomes with 15% glycolipids demonstrated better stability due to the electrostatic effect from the negatively charged SuLe a and TSuLe a headgroups. The results indicate that the biomimetic liposomes with SuLe a -and TSuLe a -lipids with 5 to 15% incorporation are sufficiently stable for the potential applications in targeted drug delivery.

show abstract

“…Indeed, both polymeric and liposome-like SLex derivatives have been shown to be much more active (by a factor of '70-5000, depending on the structure and formulation) than the monomeric species as inhibitors of E-selectin (57,96,97). The mimetics perhaps can be converted to the multivalent form to increase the activity.…”

Section: Chemoenzymatic Approaches To the Synthesis Of Complex Carbohmentioning

confidence: 99%

Intervention of carbohydrate recognition by proteins and nucleic acids.

Sears

Wong

1996

Proc. Natl. Acad. Sci. U.S.A.

113

View full text Add to dashboard Cite

Carbohydrates in biological systems are often associated with specific recognition and signaling processes leading to important biological functions and diseases. Considerable efforts have been directed toward understanding and mimicking the recognition processes and developing effective agents to control the processes. The pace of discovery research in glycobiology and development of carbohydratebased therapeutics, however, has been relatively slow due to the lack of appropriate strategies and methods available for carbohydrate-related research. This review summarizes some of the most recent developments in the field, with particular emphasis on work from our laboratories regarding the use of chemoenzymatic strategies to tackle the carbohydrate recognition problem. Highlights include the study of selectincarbohydrate and aminoglycoside-RNA interactions and development of agents for the intervention of these recognition processes.Of the three major classes of biomolecules, carbohydrates perhaps are the least exploited. It has been known that carbohydrates can serve as structural components of natural products, as energy sources, or, more interestingly, as key elements in various molecular recognition processes, including bacterial and viral infections, cell adhesion in inflammation and metastasis, differentiation, development, regulation, and many other intercellular communication and signal transduction events (1). [Representative structures are presented in Fig. 1 (2-16).] The precise mechanism of many carbohydratemediated recognition processes are, however, not well understood, and, though potential opportunities exist, the pace of development of carbohydrate-based pharmaceuticals has been slower than that of the other classes of biomolecules. Several reasons may be attributed to this slow pace of development. First, some technical problems in the field are impossible or difficult to solve. There is no PCR equivalent replication system available for the amplification of minute amounts of carbohydrates to facilitate structure analysis and synthesis, and there is no machine available for the solid-phase synthesis of oligosaccharides to facilitate the study of their functions. In addition, synthesis of oligosaccharides in large quantities for therapeutic evaluation and development is in general very difficult and expensive. Second, carbohydrates generally possess undesirable properties for drug development. The affinity of carbohydrates for their protein receptors is relatively weak (17-21), with dissociation constants in the millimolar range, and carbohydrates are generally orally inactive and sensitive to enzymes in vivo. As a result, carbohydrates may only be used as injectable form for the treatment of acute symptoms.Understanding carbohydrate recognition is important, however, as this recognition process often occurs at the early stage of disease development, and intervention of such process may be beneficial. Furthermore, understanding the mechanism of carbohydrate recognition may lead to the devel...

show abstract

Sialyl Lewis x Liposomes as a Multivalent Ligand and Inhibitor of E-Selectin Mediated Cellular Adhesion

Cited by 113 publications

References 22 publications

Nonstatistical binding of a protein to clustered carbohydrates

Nonstatistical binding of a protein to clustered carbohydrates

Vesicle size and stability of biomimetic liposomes from 3′-sulfo-Lewis a (SuLea) containing glycolipids

Intervention of carbohydrate recognition by proteins and nucleic acids.

Contact Info

Product

Resources

About