| Carbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of beta-galactoside-specific animal lectins, have been strongly implicated in inflammation and cancer. Galectin-3 is involved in carbohydrate-mediated metastatic cell heterotypic and homotypic adhesion via interaction with Thomsen-Friedenreich (TF) antigen on cancer-associated MUC1. However, the precise mechanism by which galectin-3 recognizes TF antigen is poorly understood. Our thermodynamic studies have shown that the presentation of the carbohydrate ligand by MUC1-based peptide scaffolds can have a major impact on recognition, and may facilitate the design of more potent and specific galectin-3 inhibitors that can be used as novel chemical tools in dissecting the precise role of galectin-3 in cancer and inflammatory diseases. Another lectin, odorranalectin (OL), has been recently identified from Odorrana grahami skin secretions as the smallest cyclic peptide lectin, has a particular selectivity for L-fucose and very low toxicity and immunogenicity, rendering OL an excellent candidate for drug delivery to targeted sites, such as: (1) tumor-associated fucosylated antigens implicated in the pathogenesis of several cancers, for overcoming the nonspecificity of most anticancer agents; (2) the olfactory epithelium of nasal mucosa for enhanced delivery of peptide-based drugs to the brain. Described in this dissertation is a simple and robust approach toward the solid-phase synthesis of OL and its analogs, based on standard Fmoc-solid phase peptide synthesis protocols. Lectin-cell staining studies reveal preferential binding towards cancer cell lines that overexpress fucosylated antigens on their cell surface when compared to healthy cells. In addition, our in vivo mice studies show fast intranasal delivery of OL to mouse brain in amounts detectable by mass spectrometry, thus offering a novel brain drug delivery system for the treatment of central nervous system (CNS) disorders. Altogether, the research described in this dissertation demonstrates that new 'lectin-mimicking' peptides related to lectins or their target glycans have the potential to be used: as sensors for detection, diagnosis, and prognosis, as "blockers/inhibitors" for therapeutics development, and as vectors for the targeted delivery of imaging and therapeutic agents. |
