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과불화알킬기가 도입된 변형 올리고뉴클레오타이드의 합성 및 특성 연구

Title
과불화알킬기가 도입된 변형 올리고뉴클레오타이드의 합성 및 특성 연구
Authors
양희주
Date Issued
2011
Publisher
포항공과대학교
Abstract
By the late 1970s, gene therapy was suggested as short-length nucleic acids had proven to be able to control the expression of a specific gene through specific and complementary binding to the mRNA of the gene and help disease treatment
antisense therapy, antigen therapy and ribozyme therapy. Although gene therapy has great potential, it has many limitations that must be resolved prior to its practical use
cellular membrane permeability, nuclease resistance and thermal stability. Especially, oligonucleotide has poor cellular membrane permeability since it has negatively charged phosphate backbone which increases repulsion with negatively charged phospholipids in a cell membrane. This can be overcome through conjugating positively charged moieties or lipophilic groups with the oligonucleotide. Therefore, a research using perfluoroalkyl chain as a lipophilic modification moiety to improve the cell permeability can be a novel approach for making a better gene therapy. We could anticipate higher thermal stability and hydrophobicity due to the properties of fluorine. We chose modification of C5 position not to disturb the normal hydrogen bonding between the two complimentary bases and used Sonogashira coupling and 1.3-dipolar cycloaddition to construct triazole ring. We selected the perfluorodecyl and perfluorododecyl chains in order to observe the effect of different lengths of perfluoroalkyl chain. Synthesized C5-modified nucleotide was incorporated to the stem region of hairpin structure of the DNA oligonucleotide. It has a similar shape to that of phospholipids having a hydrophilic head and a hydrophobic tail. We proved that the interactions between perfluoroalkyl chains stabilizes the hairpin structure and increase its thermal stability by NMR analysis of solution state DNA oligonucleotide. We also synthesized modified VEGF siRNAs with perfluoroalkyl chains in the sense strand with different number of chains at various positions. 3’ end modification of the sense strand showed better enzymatic stability and did not change the thermal stability. The longer and the more chains it has, the higher the RNAi efficacy. F2-End-C12 that has two perfluorododecyl chains at the 3’ end of sense strand showed the most efficient knock-down VEGF in RNAi due to the high lipophilicity and serum resistance.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000000897929
http://oasis.postech.ac.kr/handle/2014.oak/1036
Article Type
Thesis
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