Fucose-containing oligosaccharides are well documented to mediate important cell adhesion and cell communication events Including, trafficking of leukocytes, cancer metastasis, and host pathogen interactions. Blocking adhesion events involving fucosylated oligosaccharides represents a viable approach to the treatment of diverse indications such as chronic inflammatory disease and ulcers. One way to accomplish this is to prevent the synthesis of the carbohydrates themselves. A family of fucosyltransferases that are expressed in a tissue and cell type specific manner carries out attachment of fucose to carbohydrates. Thus, inhibition of a specific fucosyltransferase has the potential to be a highly selective method of disrupting cell adhesion events mediated by fucose containing carbohydrates. The proposed research is directed to characterizing the specificity and cell permeability of three new classes of fucosyltransferase inhibitors with in vitro IC50 values as low as 68 nM. Unlike previously reported inhibitors based on donor and acceptor substrates, they are uncharged, non-carbohydrate small molecule organic compounds. These inhibitors provide the basis for development of potent orally available fucosyltransferase inhibitors with potential for treatment of chronic inflammatory disease. PROPOSED COMMERCIAL APPLICATION: The fucosylated oligosaccharide sialyl-Lewis X is a key mediator of leukocyte trafficking in conditions of chronic inflammation. Thus, inhibitors of the fucosyltransferase FucT-VII are anticipated to be effective in treatment of chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis and psoriasis. Each of these conditions comprises major unmet medical needs and has the potential for mufti-billion dollar markets.
