Gapped 2' modified oligonucleotides

• US 5,955,589 A
• Filed: 06/06/1995
• Issued: 09/21/1999
• Est. Priority Date: 12/24/1991
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Monia, Brett P., Cook, Phillip Dan
• Primary Examiner(s): Low, Christopher S. F.
• Application Number:
  US08/465,880
• Time in Patent Office: 1,568 Days
• Field of Search: 536/25.32, 536/25.3, 536/25.2, 536/24.32, 536/24.31, 536/24.3, 536/24.2, 536/24.1, 536/23.1, 435/91.1, 435/91.3, 435/91.41, 935/3, 935/6, 935/8
• US Class Current: 536/23.1
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/003 Peptide-nucleic acids (PNAs)
• CPC Class Codes: C12Q 1/6813 Hybridisation assays
• CPC Class Codes: C12Q 1/6832 Enhancement of hybridisation reaction
• CPC Class Codes: C12Q 2521/319 Exonuclease
• CPC Class Codes: C12Q 2525/101 incorporating non-naturally occurring nucleotides, e.g. inosine
• CPC Class Codes: C12Q 2525/125 incorporating agents resulting in resistance to degradation

Abstract

Oligonucleotides and other macromolecules are provided which have increased nuclease resistance, substituent groups for increasing binding affinity to complementary strand, and subsequences of 2'"'"'-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H. Such oligonucleotides and macromolecules 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.

Claims

1. An oligonucleotide comprising a sequence of nucleotide unite specifically hybridizable with DNA or RNA wherein said sequence is divided into a first segment and a second segment, wherein:

said first segment is adjacent said second segment and does not overlap said second segment;

said first segment has at least two consecutively located 2'"'"'-F nucleotide units;

said second segment is composed of at least five consecutively located nucleotide units having 2'"'"'-H sugar moieties; and

said oligonucleotide hybridizes with said DNA or RNA with higher binding affinity than a corresponding oligomer in which said at least two consecutively located 2'"'"'-F nucleotide units are 2'"'"'-H nucleotide units.

2. The oligonucleotide of claim 1 wherein said nucleotide units of said first and second segments are connected by phosphodiester or phosphorothioate linkages.

3. The oligonucleotide of claim 2 wherein said nucleotide units of said first and second segments are connected by phosphodiester linkages.

4. The oligonucleotide of claim 2 wherein said nucleotide units of said first and second segments are connected by phosphorothioate linkages.

5. The oligonucleotide of claim 2 wherein said nucleotide units of said first segment are connected by phosphodiester linkages and said nucleotide units of said second segment are connected by phosphorothioate linkages.

6. The oligonucleotide of claim 2 wherein said nucleotide units of said first segment are connected by phosphorothioate linkages and said nucleotide units of said second segment are connected by phosphodiester linkages.

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

8. An oligonucleotide comprising a sequence of nucleotide units specifically hybridizable with DNA or RNA, wherein said sequence is divided into a first segment, a second segment, and a third segment wherein:

said first segment and said third segment each has at least two consecutively located 2'"'"'-deoxy-2'"'"'-fluoro nucleotide units; and

said second segment is positioned adjacent to and between said first segment and said third segment and is composed of at least three consecutively located nucleotide units having 2'"'"'-deoxy sugar moieties.

9. The oligonucleotide of claim 8 wherein said nucleotide units of said first, second and third segments are connected by phosphodiester or phosphorothioate linkages.

10. The oligonucleotide of claim 9 wherein said nucleotide units of said first, second and third segments are connected by phosphodiester linkages.

11. The oligonucleotide of claim 9 wherein said nucleotide units of said first, second and third segments are connected by phosphorothioate linkages.

12. The oligonucleotide of claim 9 wherein said nucleotide units of said first and third segments are connected by phosphodiester linkages and said nucleotide units of said second segment are connected by phosphorothioate linkages.

13. The oligonucleotide of claim 9 wherein said nucleotide units of said first and third segments are connected by phosphorothioate linkages and said nucleotide units of said second segment are connected by phosphodiester linkages.

14. The oligonucleotide of claim 8 wherein said second segment has at least five nucleotide units.

15. The oligonucleotide of claim 8 having 5 to 50 nucleotide units.