title: The discovery, biology, and drug development of sialyl Lea and sialyl Lex.
abstract: The discoveries of sialylated, fucosylated lacto-, and neolacto-type carbohydrate structures were accomplished with the aid of analytical methods and monoclonal antibodies such as the immunostaining of thin layer chromatograms. Based on the use of such antibodies, these structures, notably sialyl Le(a) and sialyl Le(x), were demonstrated to be highly expressed in many malignant cancers. A diagnostic assay using one of these antibodies (CA19-9) is now established as one of the more commonly used assays for pancreatic and gastrointestinal cancers worldwide. Upon further study, several laboratories have demonstrated that the level of expression of these carbohydrate tumor markers is also positively correlated with patient survival and is a prognostic indicator of metastatic disease. Concurrent with this finding, both sialyl Le(a) and sialyl Le(x) were shown to bind to a family of carbohydrate-binding proteins involved in the extravasation of cells from the bloodstream, called the selectins. Thus, sialyl Le(a) and sialyl Le(x) expressed on cell surfaces play functional roles in medical conditions that require extravasation of cells from the bloodstream which include a wide range of inflammatory diseases and cancer metastasis. Many studies have confirmed the function of sialyl Le(a) and sialyl Le(x) in animal models of these diseases and the inhibition of binding of sialyl Le(a) and sialyl Le(x) to the selectins is a validated drug target in the pharmaceutical industry. Thus, a new class of drugs, arising from the field of glycobiology, is based on the rational design of small molecule drugs that mimic the structures sialyl Le(a) and sialyl Le(x) and can potently inhibit their functional binding to the selectins.
authors.affiliation: GlycoMimetics Inc., 14915 Broschart Road, Rockville, MD, USA. jmagnani@glycomimetics.com
authors.forename: John L
authors.initials: JL
authors.lastname: Magnani
mesh_terms: D000818:Animals; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D018395:CA-19-9 Antigen; D015195:Drug Design; D005732:Gangliosides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D046911:Macromolecular Substances; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D009844:Oligosaccharides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D019087:Selectins / Q000737:chemistry / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D005732:Gangliosides; D046911:Macromolecular Substances; D009844:Oligosaccharides; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; C064564:sialyl Le(a) ganglioside