Sugar-modified gapped oligonucleotides

• US 6,451,991 B1
• Filed: 02/11/1997
• Issued: 09/17/2002
• Est. Priority Date: 02/14/1996
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.), Novartis Ag
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.), Novartis Ag
• Inventors: Monia, Brett P., Cook, Phillip Dan, Martin, Pierre, Altmann, Karl-Heinz
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US08/802,331
• Time in Patent Office: 2,044 Days
• Field of Search: 435/6, 436/501, 536/23.1, 536/24.1, 536/24.5, 536/24-- 2, 536/25.3, 935/77, 935/78
• US Class Current: 536/23.1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Oligonucleotides are provided which have increased nuclease resistance, substituent groups for increasing binding affinity to complementary nucleic acid strand, and subsequences of 2′-deoxy-erythro-pentofuranosyl nucleosides that activate RNase H. Such oligonucleotides 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 ooligonucleotide therapeutics.

Claims

1. An oligonucleotide specifically hybridizable with DNA or RNA said oligonucleotide comprising a linear sequence of covalently-bound nucleoside units, wherein:

said sequence comprises a first nucleoside subsequence having adjacent 2′

-O—

CH₂—

CH₂—

O—

CH₃ sugar moieties and a second nucleoside subsequence having adjacent 2′

-deoxy sugar moieties, wherein;

said nucleoside units of said first and second subsequences are covalently-bound by phosphorothioate linkages;

or

said nucleoside units of said first subsequence are covalently-bound by phosphodiester linkages and said nucleoside units of said second subsequence are covalently-bound by phophorothioate linkages;

or

said nucleoside units of said first subsequence are covalently-bound by phosphorothioate linkages and said nucleoside units of said second subsequence are covalently-bound by phosphodiester linkages.

2. The oligonucleotide of claim 1 wherein said nucleoside units of said first and second subsequences are covalently-bound by phosphorothioate linkages.

3. The oligonucleotide of claim 1 wherein said nucleoside units of said first subsequence are covalently-bound by phosphodiester linkages and said nucleoside units of said second subsequence are covalently-bound by phosphorothioate linkages.

4. The oligonucleotide of claim 1 wherein said nucleoside units of said first subsequence are covalently-bound by phosphorothioate linkages and said nucleoside units of said second subsequence are covalently-bound by phosphodiester linkages.

5. The oligonucleotide of claim 1 wherein said second subsequence comprises at least three nucleoside units.

6. The oligonucleotide of claim 1 wherein said second subsequence comprises at least five nucleoside units.

7. The oligonucleotide of claim 1 having 5 to 50 nucleoside units.

8. An oligonucleotide specifically hybridizable with DNA or RNA said oligonucleotide comprising a linear sequence of covalently-bound nucleoside units, wherein:

said sequence comprises a first nucleoside subsequence having adjacent 2′

-OCH₂—

CH₂—

O—

CH₃ sugar moieties, a second nucleoside subsequence having adjacent 2′

-deoxy sugar moieties, and a third nucleoside subsequence having adjacent 2′

-O—

CH₂—

CH₂—

O—

CH₃ sugar moieties, wherein said second subsequence is positioned between said first and third subsequences; and

the nucleoside units within said first, second, and third subsequences are covalently-bound by phosphodiester or phophorothioate linkages.

9. The oligonucleotide of claim 8 wherein said nucleoside units of said first, second and third subsequences are covalently-bound by phosphorothioate linkages.

10. The oligonucleotide of claim 8 wherein said nucleoside units of said first and thir subsequences are covalently-bound by phosphodiester linkages and said nucleoside units of said second subsequence are covalently-bound by phosphorothioate linkages.

11. The oligonucleotide of claim 8 wherein said nucleoside units of said first and third subsequences are covalently-bound by phosphorothioate linkages and said nucleoside units of said second subsequence are covalently-bound by phosphodiester linkages.

12. The oligonucleotide of claim 8 wherein said second subsequence comprises at least three nucleoside units.

13. The oligonucleotide of claim 8 wherein said second subsequence comprises at least five nucleoside units.

14. The oligonucleotide of claim 8 having 5 to 50 nucleoside units.