Synthesis of 2'-Amino-LNA: A Novel Conformationally Restricted High-Affinity Oligonucleotide Analogue with a Handle.
26 Nov 1998-Journal of Organic Chemistry (American Chemical Society)-Vol. 63, Iss: 26, pp 10035-10039
About: This article is published in Journal of Organic Chemistry.The article was published on 1998-11-26. It has received 254 citations till now. The article focuses on the topics: Bridged nucleic acid.
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TL;DR: Several reports have revealed LNA as a most promising molecule for the development of oligonucleotide-based therapeutics, including high capturing efficiencies and unambiguous scoring of single-nucleotide polymorphisms.
663 citations
Patent•
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04 May 2000
TL;DR: In this paper, a 2'-4'-bridge locks the conformation of the nucleoside with an inverted stereochemistry at C-3' and C-4' to provide the L-ribo-configurated LNA nucleosides.
Abstract: Nucleoside analogues wherein a 2'-4'-bridge locks the conformation of the nucleoside have been synthesised with an inverted stereochemistry at C-3' and C-4' to provide the L-ribo-configurated LNA nucleoside. The synthesis of L-ribo-LNA-nucleoside is applicable to all nucleobases including thymine, adenine, cytosine, guanine and uracil. These Locked Nucleic Acids (LNAs) with L-ribo-configuration have been utilised in the synthesis of 2'-O-4'-C-methylene-α-L-ribofuranosyl nucleotides as well as oligonucleotides with L-ribo-LNA nucleosides included therein. Methods of targeting complementary nucleic acids are greatly improved by use of these L-ribo-LNA modified oligonucleotides due to their high affinity for complementary nucleic acids.
551 citations
Patent•
09 Mar 1998TL;DR: An oligo- or polynucleotide analogue having one or more structures of the general formula where B is a pyrimidine or purine nucleic acid base, or an analogue thereof, is disclosed in this paper.
Abstract: An oligo- or polynucleotide analogue having one or more structures of the general formula where B is a pyrimidine or purine nucleic acid base, or an analogue thereof,
is disclosed. The use of this analogue provides an oligonucleotide analogue antisense molecule, which is minimally hydrolyzable with an enzyme in vivo, has a high sense strand binding ability, and is easily synthesized.
495 citations
Patent•
27 Jan 2007TL;DR: In this article, the 6-modified bicyclic nucleoside analogs and oligomeric compounds comprising these analogs are presented. But they do not have (R) or (S)-chirality at the 6 position.
Abstract: The present invention provides 6-modified bicyclic nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 6-position. These bicyclicnucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.
427 citations
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06 Jun 1997TL;DR: Oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics.
Abstract: Oligomeric compounds including oligoribonucleotides and oligoribonucleosides are provided that have subsequences of 2′-pentoribofuranosyl nucleosides that activate dsRNase. The oligoribonucleotides and oligoribonucleosides can include substituent groups for increasing binding affinity to complementary nucleic acid strand as well as substituent groups for increasing nuclease resistance. The oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics. Also included in the invention are mammalian ribonucleases, i.e., enzymes that degrade RNA, and substrates for such ribonucleases. Such a ribonuclease is referred to herein as a dsRNase, wherein “ds” indicates the RNase's specificity for certain double-stranded RNA substrates. The artificial substrates for the dsRNases described herein are useful in preparing affinity matrices for purifying mammalian ribonuclease as well as non-degradative RNA-binding proteins.
422 citations
References
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2,224 citations
TL;DR: Studies of mis-matched sequences show that LNA obey the Watson-Crick base pairing rules with generally improved selectivities compared to the corresponding unmodified reference strands.
1,155 citations
TL;DR: From results, structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure are determined and C-5-substituted pyrimidines stood out as substantially increasing duplex stability.
Abstract: In an effort to discover novel oligonucleotide modifications for antisense therapeutics, we have prepared oligodeoxyribonucleotides containing more than 200 different modifications and measured their affinities for complementary RNA. These include modifications to the heterocyclic bases, the deoxy-ribose sugar and the phosphodiester linkage. From these results, we have been able to determine structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure. Data for oligonucleotides containing modified pyrimidine nucleotides are presented. In general, modifications that resulted in the most stable duplexes contained a heteroatom at the 2'-position of the sugar. Other sugar modifications usually led to diminished hybrid stability. Most backbone modifications that led to improved hybridization restricted backbone mobility and resulted in an A-type sugar pucker for the residue 5'to the modified internucleotide linkage. Among the heterocycles, C-5-substituted pyrimidines stood out as substantially increasing duplex stability.
897 citations
TL;DR: A novel class of nucleic acid analogues, termed LNA (locked nucleic acids), is introduced following the Watson–Crick base pairing rules, which forms duplexes with complementary DNA and RNA with remarkably increased thermal stabilities and generally improved selectivities.
828 citations
TL;DR: Improvements in ODN chemistry and cellular delivery techniques now allow for more potent and specific gene inhibition.
Abstract: Antisense oligodeoxynucleotides (ODNs) have great promise as agents for the specific manipulation of gene expression. Until recently, nonspecific effects of ODNs often confounded the interpretation of antisense studies. Improvements in ODN chemistry and cellular delivery techniques now allow for more potent and specific gene inhibition. This review critically evaluates recent progress in the development of antisense ODNs.
825 citations