Chemical tools for glycoengineering and therapeutics. Laila Dafik

ISBN: 9780549521884

Published:

NOOKstudy eTextbook

178 pages


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Chemical tools for glycoengineering and therapeutics.  by  Laila Dafik

Chemical tools for glycoengineering and therapeutics. by Laila Dafik
| NOOKstudy eTextbook | PDF, EPUB, FB2, DjVu, audiobook, mp3, ZIP | 178 pages | ISBN: 9780549521884 | 9.40 Mb

Cell-surface glycoproteins play a pivotal role in many biological processes and mediate a number of cellular and molecular recognition events including cell-cell communication, leukocyte trafficking and cancer metastasis. Elements of the process ofMoreCell-surface glycoproteins play a pivotal role in many biological processes and mediate a number of cellular and molecular recognition events including cell-cell communication, leukocyte trafficking and cancer metastasis. Elements of the process of tumor cell adhesion are similar to leukocyte extravasation during inflammation.

In both cases, expression of branched sialic acid capped oligosaccharides, sialyl Lewis X (sLeX) and A (sLeA ), on cell surfaces is associated with their ability to adhere to E-, P-, and L-selectins. Reutter, and later Bertozzi, have successfully engineered cellular surfaces with unnatural sialic acids using the biosynthetic machinery. This approach utilizes monosaccharide precursors bearing unnatural pendant groups that are successfully processed through the various steps of the pathway and then attached to lipids and proteins.

The sialic acid biosynthetic machinery has an established tolerance towards many sialic acid and N-acetyl mannosamine (ManNAc) derivatives.-We have demonstrated the incorporation of fluorinated groups on mammalian cell surfaces using this pathway. In principle, the incorporation of fluorinated mannosamine and/or sialic acid derivatives could lead to generation of non-stick mammalian cells. Fluorinated mammalian cells could exhibit anti-metastatic phenotypic properties, which could provide leads in the development of new drug candidates. To this end, we have tested multiple fluorinated substrates with respect to their ability to be incorporated on mammalian cell surface proteins and/or lipids.-Incorporation of fluorinated sialic acids lead to dramatic decreases in adhesion to plates coated with fibronectin, and E- or P-selectin.

These results suggest that alteration of cell surfaces may lead to potential therapeutic leads, since cell migration adhesion and recognition are linked to metastatic behavior. Furthermore, early detection of tumors and metastasis by 19F MRI would be an added benefit.-The second part of this thesis explores the use of fluorocarbon lipids as vehicles for macromolecule delivery into mammalian cells.

The Kumar group has recently demonstrated that fluorinated phospholipids form phase-separated microdomains when mixed with natural hydrocarbon lipids. We are interested in studying the effect of this phase separation on the internalization efficiency of macromolecules conjugated to fluorinated phospholipids serving as delivery vehicles.

We designed phospholipids molecules that contain an H-phosphonate handle, which could be used for further functionalization. We have shown that partially fluorinated lipid and their hydrocarbon counterparts conjugated to the fluorophore 7-nitrobenz-2oxa-1,3-diazole (NBD), can cross Jurkat, HL60 and HeLa cell membranes.-Inspection of treated cells by fluorescence microscopy revealed that the dye-lipid conjugates were distributed both on the cell membrane and in the cytosol. The observed increase of fluorescence was concentration dependent.

Similar studies were conducted using fluorinated lipid-biotin conjugates. The uptake of the latter was followed by probing with avidin conjugated to FITC complexed noncovalent to biotin. The distribution of the biotin-lipid conjugate was similar to the one observed in the case of the NBD-lipid conjugate. The internalization of the lipids was energy dependent, suggesting that the uptake is mediated via endocytosis.



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