Multivalent Glycoconjugates to Modulate Carbohydrate-protein Interactions (CPIs)

Abstract

Carbohydrate-protein interactions (CPIs) are one of the most important and major events on cell surfaces. Basic components involved in the interaction are the cell surface glycans, which demonstrate a sensitive and selective cis/trans binding with protein counterparts. However, due to weak CPIs, nature facilitates multivalency to target specific proteins. Recently, extensive efforts have been directed toward mimicking these bio-events by replicating the multivalent scaffolds. Significant progress has been achieved in this regard using multivalent glycoprobes. However, other important issues regarding the preparation of multivalent carbohydrates are related to the size, shape, orientation, and local concentration of the sugars with respect to external stimuli. In the following chapters, we have investigated the role of different shapes in carbohydrate-mediated interactions. Chapter 1 summarizes different multivalent scaffolds and their major applications in targeting carbohydrate-protein interactions. We highlighted the current efforts made in the synthesis of glycodendrimers, glycopeptides, metallo-glycodendrimers, glyconanoparticles, and supramolecular complexes and the role of spatial arrangements, chirality, and symmetry of these multivalent probes in carbohydrate-protein interactions. Finally, we discuss shape-dependent biological interactions that have been reported in literature. Chapter 2 describes the synthesis of glyco-gold nanoparticles of three different shapes and their applications in bacterial aggregations and infection. More specifically, we have compared the behavior of nanospheres, nanorods and nanostars with mannose and galactose conjugations. The mechanism of aggregation revealed that the large number of surface interaction of rod shaped mannose-AuNPs with E.coli ORN 178 compared with spherical and star-shaped AuNPs. Moreover, such sensitive binding can be used for effective inhibition of bacterial infection of cells. Chapter 3 deals with the shape dependent uptake of glyco-gold nanoparticles (G-AuNPs) by different cancer cell lines. In vitro experiments once again showed that rod-AuNPs exhibited the highest uptake than that of the star and spherical counterparts. Further investigation of the mechanism of uptake clearly demonstrated clathrin mediated endocytosis of the specific G-AuNPs. Overall, these results revealed the benefits of different shapes in carbohydrate-mediated interactions. xiv Chapter 4 reports a systematic evaluation of the toxicity, biodistribution of fluorescently tagged mannose -AuNPs of three different shapes (sphere, rod, and star) in the adult zebrafish model, which could accelerate and provide preliminary results for further experiments in the higher order animal system. ICP-MS analysis and confocal images of various zebrafish organs revealed that shape and different carbohydrates on AuNPs show noticeable different in the rate of biodistribution and clearance of G-AuNPs. Among the different shapes, rod-AuNPs exhibited the fast uptake, while, star-AuNPs displayed prolong sequestration, demonstrating its potential therapeutic efficacy in drug delivery. These findings provide new insight into the use of the zebrafish as a potential in vivo system to study glyco-materials.