Insights from Crystal Structures into the Opposite Effects on RNA Affinity Caused by the S- and R-6鈥?Methyl Backbone Modifications of 3鈥?Fluoro Hexitol Nucleic Acid

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• 作者：Pradeep S. Pallan ; Jinghua Yu ; Charles R. Allerson ; Eric E. Swayze ; Punit Seth ; Martin Egli
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：January 10, 2012
• 年：2012
• 卷：51
• 期：1
• 页码：7-9
• 全文大小：220K
• 年卷期：v.51,no.1(January 10, 2012)
• ISSN：1520-4995

文摘

Locked nucleic acid (LNA) analogues with 2鈥?4鈥?bridged sugars show promise in antisense applications. S-5鈥?Me-LNA has high RNA affinity, and modified oligonucleotides show weakened immune stimulation in vivo. Conversely, an R-5鈥?methyl group dramatically lowers RNA affinity. To test the effects of S- and R-6鈥?methyl groups on 3鈥?fluoro hexitol nucleic acid (FHNA) stability, we synthesized S- and R-6鈥?Me-FHNA thymidine and incorporated them into oligo-2鈥?deoxynucleotides. As with LNA, S-6鈥?Me is stabilizing whereas R-6鈥?Me is destabilizing. Crystal structures of 6鈥?i>-Me-FHNA-modified DNAs explain the divergent consequences for stability and suggest convergent origins of these effects by S- and R-6鈥?Me (FHNA) [-5鈥?Me (LNA and RNA)] substituents.