Backbone-modified oligonucleotide analogs and methods for using same

• US 20020183502A1
• Filed: 05/24/2002
• Published: 12/05/2002
• Est. Priority Date: 05/21/1991
• Status: Abandoned Application

• Current Assignee: Adrian Waldner, Alain De Mesmaeker, Jacques Lebreton, Phillip Dan Cook
• Original Assignee: Adrian Waldner, Alain De Mesmaeker, Jacques Lebreton, Phillip Dan Cook
• Inventors: Lebreton, Jacques, Cook, Phillip Dan, Mesmaeker, Alain De, Waldner, Adrian
• Application Number:
  US10/155,950
• Publication Number:
  US 20020183502A1
• Time in Patent Office: Days
• US Class Current: 536/23.1
• CPC Class Codes: A61K 49/0006 Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• 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

Therapeutic oligonucleotide analogs which have improved nuclease resistance and improved cellular uptake are provided. Replacement of phosphorodiester inter-sugar linkages found in wild type oligomers with four atom linking groups forms unique di- and poly-nucleosides and nucleotides useful in regulating RNA expression and in therapeutics. Methods of synthesis and use are also disclosed.

Claims

1. An oligonucleotide analog in which at least some of the subunits of the analog have the structure:

2. The oligonucleotide analog of claim 1 wherein Q is O.

3. The oligonucleotide analog of claim 1 wherein X is H.

4. The oligonucleotide analog of claim 1 wherein X is OH.

5. The oligonucleotide analog of claim 1 wherein X is H, OH, F, O-alkyl or O-alkenyl and Q is O.

6. The oligonucleotide analog of claim 1 wherein B_X is adenine, guanine, uracil, thymine, cytosine, 2-aminoadenosine or 5-methylcytosine.

7. The oligonucleotide analog of claim 1 comprising from about 4 to about 50 subunits having said structure.

8. The oligonucleotide analog of claim 1 wherein substantially all of the subunits have said structure.

9. The oligonucleotide analog of claim 1 wherein substantially alternating subunits have said structure.

10. The oligonucleotide analog of claim 1 wherein substantially random subunits have said structure.

11. The oligonucleotide analog of claim 1 in a pharmaceutically acceptable carrier.

12. The oligonucleotide analog of claim 1 which exhibits improved nuclease resistance as compared to corresponding wild type oligonucleotides.

14. The compound of claim 13 wherein Q is O.

15. The compound of claim 13 wherein X is H.

16. The compound of claim 13 wherein X is OH.

17. The compound of claim 13 wherein X is H, OH, F, O-alkyl or O-alkenyl and Q is O.

18. The compound claim 13 wherein B_X is adenine, guanine, uracil, thymine, cytosine, 2-aminoadenosine or 5-methylcytosine.

13. A compound having the structure:

19. A process for preparing a compound having the structure:

20. A method for modulating the production or activity of a protein in an organism comprising contacting the organism with an oligonucleotide analog specifically hybridizable with at least a portion of a nucleic acid sequence coding for said protein, wherein at least some of the subunits of the analog have the structure:

21. A method for treating an organism having a disease characterized by the undesired production of a protein comprising contacting the organism with an oligonucleotide analog hybridizable with at least a portion of a nucleic acid sequence coding for said protein, either alone or in a pharmaceutically acceptable carrier, wherein at least some of the subunits of the analog have the structure: