| Configuration of the 5'-Methyl Group Modulates the Biophysical and Biological Properties of Locked Nucleic Acid (LNA) Oligonucleotides. | |
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MedLine Citation:
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PMID: 21058707 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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As part of a program aimed at exploring the structure- activity relationships of 2',4'-bridged nucleic acid (BNA) containing antisense oligonucleotides (ASOs), we report the synthesis and biophysical and biological properties of R- and S-5'-Me LNA modified oligonucleotides. We show that introduction of a methyl group in the (S) configuration at the 5'-position is compatible with the high affinity recognition of complementary nucleic acids observed with LNA. In contrast, introduction of a methyl group in the (R) configuration reversed the stabilization effect of LNA. NMR studies indicated that the R-5'-Me group changes the orientation around torsion angle γ from the +sc to the ap range at the nucleoside level, and this may in part be responsible for the poor hybridization behavior exhibited by this modification. In animal experiments, S-5'-Me-LNA modified gapmer antisense olignucleotides showed slightly reduced potency relative to the sequence matched LNA ASOs while improving the therapeutic profile. |
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Authors:
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Punit P Seth; Charles R Allerson; Andrew Siwkowski; Guillermo Vasquez; Andres Berdeja; Michael T Migawa; Hans Gaus; Thazha P Prakash; Balkrishen Bhat; Eric E Swayze |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2010-11-8 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: - Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Medicinal Chemistry. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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