Comparing In Vitro and In Vivo Activity of 2′-O-[2-(Methylamino)-2-oxoethyl]- and 2′-O-Methoxyethyl-Modified Antisense Oligonucleotides
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- 作者：Thazha P. Prakash ; Andrew M. Kawasaki ; Edward V. Wancewicz ; Lijiang Shen ; Brett P. Monia ; Bruce S. Ross ; Balkrishen Bhat ; Muthiah Manoharan
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：May 8, 2008
- 年：2008
- 卷：51
- 期：9
- 页码：2766 - 2776
- 全文大小：1031K
- 年卷期：v.51,no.9(May 8, 2008)
- ISSN：1520-4804
文摘
A number of 2′-O-modified antisense oligonucleotides have been reported for their potential use in oligonucleotide-based therapeutics. To date, most of the in vivo data has been generated for 2′-O-MOE (2′-O-methoxyethyl)- and 2′-O-Me (2′-O-methyl)-modified ASOs (antisense oligonucleotides). We now report the synthesis and biological activity of another 2′-O-modification, namely 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA). This modification resulted in an increase in the affinity of antisense oligonucleotides to complementary RNA similar to 2′-O-MOE-modified ASOs as compared to first-generation antisense oligodeoxynucleotides. The ASO modified with 2′-O-NMA reduced expression of PTEN mRNA in vitro and in vivo in a dose-dependent manner similar to 2′-O-MOE modified ASO. Importantly, toxicity parameters such as AST, ALT, organ weights, and body weights were found to be normal similar to 2′-O-MOE ASO-treated animal models. The data generated in these experiments suggest that 2′-O-NMA is a useful modification for potential application in both antisense and other oligonucleotide-based drug discovery efforts.