TAILIEUCHUNG - Báo cáo khoa học: Antisense technologies Improvement through novel chemical modifications

Antisense agents are valuable tools to inhibit the expression of a target gene in a sequence-specific manner,and may be used for functional genomics,target validation and typesof anti-mRNAstrategies canbe distinguished. Firstly,the use of single stranded antisense-oligonucleotides; secondly,the triggering of RNA cleavage through catalytically active oligonucleotides referred to as ribozymes; and thirdly,RNA interference induced by small interfering RNA molecules. | Eur. J. Biochem. 270 1 4 2003 FEBS 2003 doi REVIEW ARTICLE Antisense technologies Improvement through novel chemical modifications Jens Kurreck Institut fur Chemie-Biochemie Freie Universitat Berlin Germany Antisense agents are valuable tools to inhibit the expression of a target gene in a sequence-specific manner and may he used for functional genomics target validation and thrra-peutic purposes. Three types of anti-mRNA strategies can be distinguished. Firstly the uee of nagle tli anded anilgang1-oligonucleotides secondly the raggering c f RNA deavage through catalytically active oligonucleotides referred to as ribozymes and thirdly RNA i nteiference i nd need by small interfering RNA molecules. Despite the seemingly simple idea to reduce translation by oligonucleotides complementary to an mRNA several problems have to be overcome for successful application. Accessible sites of the target RNA for oligonucleotide binding have to be identified antisense agents have to be protected against nucleolytic attack and their cellular uptake and correct intracellular localization have to be achieved. Major disadvantages of commonly used phosphorothioate DNA oligonucleotides are their low affinity towards target RNA molecules and their toxic sideeffects. Some of these problems have been solved in second generation nucleotides with alkyl modifications at the 2 position of the ribose. In recent years valuable progress has been achieved through the development of novel chemically modified nucleotides with improved properties such as enhanced serum stability higher target affinity and low toxicity. In addition RNA-cleaving ribozymes and deoxyribozymes and die US ơi 21-mrr dollble-tlranded RNA molecules for RNA interference applications in mammalian cells offer highly efficient strategies to suppress the expression of a specific gene. Keywords antisense-oligonucleotides deoxyribozymes DNA enzymes locked nucleic acids peptide nucleic acids .

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