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Review Intervention of Carbohydrate Recognition by Proteins and Nucleic Proc. Natl. Acad. Sci. USA Vol. 93, pp. 12086-12093, October 1996 Review Intervention of carbohydrate recognition by proteins and nucleic acids Pamela Sears and Chi-Huey Wong Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 ABSTRACT Carbohydrates in biological systems are of- zymatic methods for the synthesis of complex carbohydrates, ten associated with specific recognition and signaling pro- carbohydrate mimetics and inhibitors of enzymes associated cesses leading to important biological functions and diseases. with carbohydrate biosynthesis and processing (with particular Considerable efforts have been directed toward understand- focus on the work from our laboratories regarding the devel- ing and mimicking the recognition processes and developing opment of inhibitors that target carbohydrate interaction with effective agents to control the processes. The pace ofdiscovery selectins), RNA, and glycosyltransferases. research in glycobiology and development of carbohydrate- based therapeutics, however, has been relatively slow due to Selectins and Their Carbohydrate Ligands in Cell Adhesion the lack of appropriate strategies and methods available for carbohydrate-related research. This review summarizes some In 1989, a new class of carbohydrate binding glycoproteins of the most recent developments in the field, with particular called selectins were identified on the surface of certain cells, emphasis on work from our laboratories regarding the use of and subsequently these glycoproteins were designated as E- chemoenzymatic strategies to tackle the carbohydrate recog- (22), P- (23) and L-selectin (24, 25), according to the cell type nition problem. Highlights include the study of selectin- on which the selectin was found (i.e., endothelium, platelets, carbohydrate and aminoglycoside-RNA interactions and de- and lymphocytes, respectively). Each selectin was found to velopment of agents for the intervention of these recognition contain an N-terminal calcium-dependent lectin-like domain, processes. an epidermal growth factor repeat, and a number of modules ("60 aa) similar to those found in certain complement binding Of the three major classes of biomolecules, carbohydrates proteins (26). The x-ray structure ofhuman E-selectin has been perhaps are the least exploited. It has been known that determined (27), and its primary sequence is homologous to carbohydrates can serve as structural components of natural another structurally known sugar binding protein, the mannose products, as energy sources, or, more interestingly, as key binding protein (28). The carbohydrate ligands that are rec- elements in various molecular recognition processes, including ognized by these selectins have also been identified. E-selectin bacterial and viral infections, cell adhesion in inflammation recognizes sialyl Lewis X (SLeX) on the surface of neutrophils and metastasis, differentiation, development, regulation, and (29-31). P-selectin also binds SLeX on neutrophils or leuko- many other intercellular communication and signal transduc- cytes with a lower affinity (32, 33). L-selectin weakly recog- tion events (1). [Representative structures are presented in nizes SLex on endothelial cells, but the affinity is higher with Fig. 1 (2-16).] The precise mechanism of many carbohydrate- a sulfate group on the six position of Gal (34, 35) or, perhaps mediated recognition processes are, however, not well under- more likely, on the six position of the GlcNAc residue (33, 36). stood, and, though potential opportunities exist, the pace of Some sulfated Lex also bind to E- and P-selectin (37), and development of carbohydrate-based pharmaceuticals has been questions regarding the real ligands for P- and L-selectin still slower than that of the other classes of biomolecules. Several exist. reasons may be attributed to this slow pace of development. The selectin-carbohydrate interaction occurs at the very First, some technical problems in the field are impossible or early stage of inflammatory reaction (38, 39) or metastasis difficult to solve. There is no PCR equivalent replication (40-42). For example, as illustrated in Fig. 2, when tissue system available for the amplification of minute amounts of injury occurs, cytokines are released to signal endothelial cells carbohydrates to facilitate structure analysis and synthesis, and to synthesize E-selectins to recruit neutrophils to the site of there is no machine available for the solid-phase synthesis of injury. This process is mediated by the adhesion of neutrophils oligosaccharides to facilitate the study of their functions. In to endothelial cells through the multivalent interaction of SLeX addition, synthesis of oligosaccharides in large quantities for and E-selectin on the respective cell surface, followed by a therapeutic evaluation and development is in general very more tight interaction between integrins on neutrophils and difficult and expensive. Second, carbohydrates generally pos- the intracellular adhesion molecule (ICAM-1) on endothelial sess undesirable properties for drug development. The affinity cells, which then allows the extravasation of neutrophils to the of carbohydrates for their protein receptors is relatively weak site of injury. It is not clear how the recognition signal is (17-21), with dissociation constants in the millimolar range, transduced from outside to inside the cell, though one possi- and carbohydrates are generally orally inactive and sensitive to bility is through the integrin-FAK-Src pathway (43-45). When enzymes in vivo. As a result, carbohydrates may only be used too many neutrophils are recruited, however, normal cells will as injectable form for the treatment of acute symptoms. also be damaged, causing inflammation. Control of this pro- Understanding carbohydrate recognition is important, how- cess by adequately inhibiting the adhesion step has thus been ever, as this recognition process often occurs at the early stage considered to be a new antiinflammatory strategy, and many of disease development, and intervention of such process may acute inflammatory symptoms, such as asthma, myocardial be beneficial. Furthermore, understanding the mechanism of infarction, lung injury, and arthritis, may be treated with this carbohydrate recognition may lead to the development of new approach. Similarly, new anticancer agents could be developed concepts and new strategies to tackle the problems of carbo- based on the inhibition of this adhesion process. Indeed, the hydrate-based drug development. This review highlights the most recent work on the development of practical chemoen- Abbreviation: SLeX, sialyl Lewis X. 12086 Downloaded by guest on September 28, 2021 Review: Sears and Wong Proc. Natl. Acad. Sci. USA 93 (1996) 12087 NH2 HO4O HOH NH2 HO H2N H2 H2N 2 HO 0 Calicheamicin y,I Erythromycin A (Antibiotic)5 Neomycin B (DNA claving anticancer agent)2-4 (inhibitor d the HIV RNA Rev response element)s H OOH HOOH 0 HCiOH 0 HO OH H3C ~OH NH NHAc HO,OH | HO OH OH HO OH OH HOH H02C O OZ4OR 0~~~ HO 0 A _ _O-.0 OR HAc 0 HO HO OH (3-) NHAc HO CH3 jOH HOO HOH HOOH Sialyl Lewis X (E,P Selctin Ligand) Leb Helicobacter pylori receptor7 Tunicamycin Sialyl Lewis X 6-sulfate (L Selectin Ligand) (iinhibitor of GIcNAc phosphotransferase)8 HO OH HO OH HO OH OH H 4 o0 O0 CO2H O NHAc HO OH OH CH3 OH NHAc OHHO 0q- ( H OOHHO Cer n Breast Cancer Antigen910 hyaluronic acid1 OH OSO3H OHO AcHNI %S HO~ 0 OH 0S03H H02C OS%3H lto OH HO O _ HH HO HO OCrCe HO3SHN0 HO Heparin pentasaccharide12 E. coliShiga Toxin Receptor13 0 OH Lipid A14 HO H02C RIO OH O HO OH 0OH OH HOOH~ ~ ~ ~ O }AcHH-O~~~~~~~~~OSC>sHq-go Z,3 1327 HO1 ; 4 4~ O4OCer OH HO Ganglioside GM1: R1 = GalfJl-3GaINAcJO-,R2 = H Antigen of Major Antibody in Xenotransplantation16 Ganglioside GM2: R1 = GalNAc,B-, R2 = H Ganglioside GM3: R1 = H, R2 = H Ganglioside GD3: R1 = H, R2 = NeuAcH- 9-0-Ac GD3 (Melanoma antigen)15 FIG. 1. Representative naturally occurring complex carbohydrates and conjugates with important biological activities. carbohydrate ligands of these selectins, especially that of E- are essential for binding, and that the GlcNAc residue is not and P-selectin, have been shown to be potentially useful in the critical (57). For P-selectin, the essential functional groups are treatment of these acute symptoms (46, 47). generally the same except that the 2- or 4-hydroxyl group of fucose seems not to be critical (54). These discoveries together Chemoenzymatic Approaches to the Synthesis of Complex with the conformation of SLeX determined by NMR (58-61) Carbohydrates, Glycopeptides, and Glycoproteins provide a basis for the design of new structures to mimic the active conformation of SLex, which may lead to the discovery the of and related of new and better antiinflammatory agents. The chemistry developed for synthesis SLeX The conformation of SLeX in solution (58) is different from structures (48-53) has played a very important role in the study that bound to E-selectin (61), especially the orientation of the of structure-function relationship. It has not only confirmed neuraminic acid residue (Fig. 3). The energy difference of the function of the ligand but also unraveled the essential these two conformations is estimated to be -1.5 kcal/mol (62), groups of ligand involved in recognition. In the case of E- and suggesting that it is possible to design a conformationally L-selectin-SLex interaction, it has been shown that the three constrained SLeX mimetic to improve the inhibition potency. hydroxy groups of fucose (54, 55), the 2- and 6-hydroxyl groups With regard to the synthesis of SLex, enzymatic methods of galactose (56) and the carboxylate of neuraminic acid (54) have been developed for the large-scale process (58). The use Downloaded by guest on September 28, 2021 12088 Review: Sears and Wong Proc. Natl. Acad. Sci. USA 93 (1996) FIG. 2. SLex-mediated cell adhesion in inflammatory reaction. FIG. 3. Overlay of the solution conformation of SLeX and that bound to the receptor E-selectin, determined by NMR.
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