Structure, selectin

These interactions involve adhesion proteins called selectins, which are found both on the rolling leukocytes and on the endothelial cells of the vascular walls. Selectins have a characteristic domain structure, consisting of an N-terminal extracellular lectin domain, a single epidermal growth factor (EGR) domain, a series of two to nine short consensus repeat (SCR) domains, a single transmembrane segment, and a short cytoplasmic domain. Lectin domains, first characterized in plants, bind carbohydrates... 

The three selectins are related both structurally and functionally. They are transmembrane proteins, with an N-terminal C-type actin domain, followed by an EGF repeat and a variable number of complement control protein (CCP) domains. Selectins bind carbohydrates, which are present in various glycoproteins. 

Figure 47-10. Schematic diagram of the structure of human L-selectin. The extracellular portion contains an amino terminal domain homologous to C-type lectins and an adjacent epidermal growth factor-like domain. These are followed by a variable number of complement regulatory-like modules (numbered circles) and a transmembrane sequence (blackdiamond). A short cytoplasmic sequence (open rectangle) is at the carboxyl terminal. The structures of P- and E-selectin are similar to that shown except that they contain more complement-regulatory modules.The numbers of amino acids in L-, P-, and E- selectins, as deduced from the cDNA sequences, are 385,789, and 589, respectively. (Reproduced, with permission, from Bevilacqua MP, Nelson RM Selectins. J Clin Invest 1993 91 370.)...

The precise chemical nature of some of the ligands involved in selectin-ligand interactions has been determined. All three selectins bind sialylated and fucosy-lated oligosaccharides, and in particular all three bind sialyl-Lewis (Figure 47-12), a structure present on both glycoproteins and glycolipids. Whether this compound is the actual ligand involved in vivo is not estab-... 

A similar approach was used in the synthesis of the sialyl Lewis X mimetics of type 85 (Scheme 13.22).66 Protein crystallization,67 conformational studies of sLex in solution68 and in bound form to E- and P-selectin69 as well as the study of structure-function relationships70,71 gave information about the functional groups of the sLex-epitope essential for the binding to the selectins. Synthesized mimetics must contain the three essential hydroxyl functions of the fucose. Sialic acid, galactose, and... 

Lex-antigenic trisaccharide (a-L-Fuc(l-3)-[p-D-Gal-(l-4)-p-D-GlcNAc]) and its sialylated structure (SLex) are terminal components of a nnmber of glycoconjugates on cell surfaces [31]. SLex serves as a ligand for the endothelial leukocyte molecule-1 (E-selectin) [32], which mediates the initial stages of adhesion of leukocytes to activated endothelial cells, and pays a critical role during inflammatory responses [33]. Lex-based carbohydrates have shown promise in therapeutic investigations related to the inflammatory process. As a result, extensive efforts have been directed toward the synthesis of SLex and related molecules [34 also see Chap. 15],... 

A number of functional sialyl Lewis mimetics have been synthesized. Their activities in vitro are equal or even better than those of the tetrasac-charide itself. To overcome synthetic problems, efficient stereoselective glycosylations as well as new chemoenzymatic methods for C-C bond formations had to be developed. The substitution of neuraminic acid by (5)-phenyl- and (5)-cyclohexyl lactic acid, as less flexible glycol acid residues, turned out to be very successful [10]. Also, a phosphate and a sulfate group, respectively, mimic neuraminic acid without loss of activity [11]. (5)-Cyclohexyl lactic acid-mimetic 2 shows a more than ten-fold efficacy compared with sialyl Lewis, whereas the corresponding (/ )-isomer 3 is almost inactive [10]. The deviating orientation of the carboxylic acid functionality compared to the bioactive sialyl Lewis conformation leads to the examined loss of activity. It was shown by transfer-NOE measurements of the corresponding E-selectin complexes that the coordinates of the bioactive conformation of sialyl Lewis and of compound 2 are similar. Con.se-quently structure 2 should bind to E-selectin in the same manner as that of sialyl Lewis [ 10a, b]. 

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