Selectin ligands

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-... 

Cancer Increased branching of cell surface glycans or presentation of selectin ligands may be important in metastasis. 

Harms G, Kraft R, Grelle G, Volz B, Dernedde J, Tauber R (2001) Identification of nucleolin as a new L-selectin ligand. Biochem J 360 531-538... 

A. Varki, Selectin ligands, Proc. Natl. Acad. Sci., 91 (1994) 7390-7397. 

After infection and immune cell activation, endothelial cells are variously activated to bind peripheral blood leucocytes. Bacterial toxins such as lipopolysaccharide (LPS), inflammatory cytokines such as tumour necrosis factors a and (5 (TNFa and TNFP) and interleukin-1 (5 (IL-ip) increase the synthesis of cell surface E- and P-selectins in endothelial cells. Histamine and thrombin increase PM P-selectins in endothelial cells and platelets. L-selectins are constitutively expressed in monocytes and lymphocytes. The selectins are involved in the initial adhesion of leucocytes with endothelial cells via selectin-selectin receptor interactions, for example, monocyte L-selectin-endothelial L-selectin ligand binding and T-lymphocyte-endothelial selectin-integrin interactions. This initial phase of leucocyte-endothelial adhesion enables an early stage of leucocyte rolling through successive formation and breakage of adhesive interactions. 

ESL-1 = E-.selectin-ligand-l M. Steegmaier, A. Levinowitz, S. Isenmann, E. Borges, M. Lenter, H. Kocher, B. Kleuser, D. Verstweber, Nature... 

P-selectin plays an essential role in the initial recruitment of leukocytes. When endothelial cells are activated by molecules such as histamine or thrombin during inflammation, P-selectin moves from an internal cell location to the endothelial cell surface. Thrombin is one trigger of endothelial-cell release of P-selectin. Ligands for P-selectin on eosinophils and neutrophils are similar they are sialylated carbohydrates, but clearly different from those reported for E-selectin. P-selectin attaches to the actin cytoskeleton through anchor proteins. 

Mitoma J, Petryniak B, Hiraoka N, Yeh JC, Lowe JB, Fukuda M. Extended core 1 and core 2 branched O-glycans differentially modulate sialyl Lewis X-type L-selectin ligand activity. J. Biol. Chem. 2003 278(11) 9953-9961. 

All drug-discovery approaches have so far been focused on blocking the lectin domain. Given that the role of the EGF and CR domains in ligand binding is still unclear [109], our structural considerations will concentrate exclusively on the lectin domain and the selectin ligands. 

We have further explored hydrophobic interactions during our search for high-affinity selectin ligands. Selected examples are shown in Figure 16.25 [115]. Whereas the sulfonamide derivative... 

An interesting contribution to the former strategy was made by Martens et al. [158], who screened recombinant peptide libraries to identify and optimize novel E-selectin ligands. 

A number of different competitive cell-free and cell-based binding assays under static and hydrodynamic flow conditions have been used to obtain affinity data for selectin ligands. In addition to the fact that different positive controls have been used, this makes a direct comparison of reported binding affinities difficult. Therefore, in this chapter, we quote relative affinities wherever possible (Section 16.4.3). Another problem that has a negative effect on assay reliabihty has been encountered in cases where acidic ion exchange resins are used in the final step of the antagonist synthesis [170]. Small amounts of polyanions released from the resin were found to be potent selectin inhibitors, especially for P-selectin. These polyanions are difficult to remove and are not detectable by routine analysis. As a result, published assay data for P-selectin antagonists should be considered with caution. 

Entry P-Selectin Ligand P-Selectin Blocking Agent Incubation Time Incubation Temperature References... 

Wild, M K, Huang, M.-C., Schulze-Horsel, U, van der Merwe, P A, Vestweber, D, Affinity, kinetics and thermodynamics of E-selectin binding to E-selectin ligand-1, J. Biol Chem., 276, 31602-31612, 2001. 

Tsujishita, H, Hiramatsu, Y, Kondo, N, Ohmoto, H, Kondo, H, Kiso, M, Hasegawa, A, Selectin-ligand interactions revealed by molecular dynamics simulation in solution, J. Med. Chem., 40, 362-369, 1997. 

Fukuda, M N, Ohyama, C, Lowitz, K, Matsuo, O, Pasqualini, R, Ruoslahti, E, Fukuda, M, A peptide mimic of E-selectin ligand inhibits sialyl Lewis -dependent lung colonization of tumor cells. Cancer Res., 60, 450-456, 2000. 

Renkonen, R, Fukuda, M N, Petrov, L, Paavonen, T, Renkonen, J, Hayry, P, Fukuda, M, A peptide mimic of selectin ligands abolishes in vivo inflammation but has no effect on the rat heart allograft survival. Transplantation, 74, 2-6, 2002. 

Wein, M, Sterbinsky, S A, Bickel, C A, Schleiner, R P, Bochner, B S, Comparison of human eosinophil and neutrophil ligands for P-selectin ligands for P-selectin differ from those for E-selectin, Am. J. Respir. Cell. Mol, 12, 315-319, 1995. 

Inhibition of the selectin-ligand interactions is an attractive strategy for treating inflammation-related diseases [173,174,175]. As such, sLe has been intensively used as lead structure for development of anti-inflammatory drugs both in industry and academia [176,177,178]. 

---