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Biochim Biophys Acta. 1999 Dec 10;1489(1):117-30.

2'-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation.

Author information

1
Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, CA 92008, USA. mmanohar@isisph.com

Abstract

The 2'-position of the carbohydrate moiety has proven to be a fertile position for oligonucleotide modifications for antisense technology. The 2'-modifications exhibit high binding affinity to target RNA, enhanced chemical stability and nuclease resistance and increased lipophilicity. All high binding affinity 2'-modifications have C3'-endo sugar pucker. In addition to gauche effects, charge effects are also important in determining the level of their nuclease resistance. Pharmacokinetic properties of oligonucleotides are altered by 2'-conjugates. For certain modifications (e.g., 2'-F), the configuration at the 2'-position, arabino vs. ribo, determines their ability to activate the enzyme RNase H.

PMID:
10807002
DOI:
10.1016/s0167-4781(99)00138-4
[Indexed for MEDLINE]

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