Oligonucleotides comprising alternating segments and uses thereof

Patent metadata

Field	Value
Publication number	US-9902953-B2
Application number	US-201213599520-A
Country	US
Kind code	B2
Filing date	Aug 30, 2012
Priority date	Feb 1, 2002
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

The invention relates to oligonucleotides having alternating segments of sugar-modified nucleosides and 2′-deoxynucleosides, and uses thereof. The invention further related to oligonucleotides having alternating segments of sugar-modified nucleotides and 2′-deoxynucleotides, and uses thereof. Such uses include the preparation of antisense oligonucleotides and their use for the prevention or depletion of function of a target nucleic acid of interest, such as an RNA, in a system. Accordingly, and oligonucleotide of the invention is useful for therapeutic, analytical and diagnostic methods and uses, as well as component of compositions and commercial packages corresponding to such methods and uses.

First claim

The invention claimed is:

1. An oligonucleotide comprising alternating first and second segments, wherein:
said first segment consists of all arabinonucleotides and comprises at least one arabinonucleotide,
said second segment consists of all 2′-deoxyribonucleotides and comprises at least one 2′-deoxyribonucleotide,
said oligonucleotide comprises at least 2 of each of said first and second segments thereby comprising at least 4 alternating segments, wherein the number of residues within each first segment and each second segment may be the same or variable from one segment to another,
at least one first segment comprises at least two arabinonucleotides, and
all internucleotide linkages of the oligonucleotide consist of one or more linkages selected from the group consisting of:
a) phosphotriester;
b) phosphorothioate;
d) phosphorodithioate;
d) Rp-phosphorothioate;
e) Sp-phosphorothioate;
f) boranophosphate;
g) 3′thioformacetal;
h) methylene (methylimino);
i) amide;
j) methylphosphonate;
k) phosphoramidate (5′P—N3′); and
l) any combination of (a) to (k).

2. The oligonucleotide of claim 1 , wherein said oligonucleotide is capable of adopting a DNA-like conformation.

3. The oligonucleotide of claim 1 , wherein said first and second segments each independently consist of 1 to 6 arabinonucleotides or 2′-deoxyribonucleotides, respectively.

4. The oligonucleotide of claim 3 , wherein said first and second segments each independently consist of 2 to 5 arabinonucleotides or 2′-deoxyribonucleotides, respectively.

5. The oligonucleotide of claim 4 wherein said first and second segments each independently consist of 3 to 4 arabinonucleotides or 2′-deoxyribonucleotides, respectively.

6. The oligonucleotide of claim 5 , wherein said first and second segments each consist of 3 arabinonucleotides or 2′-deoxyribonucleotides, respectively.

7. The oligonucleotide of claim 1 , wherein said oligonucleotide has a structure selected from the group consisting of:
a) (A x -D y ) n I;
b) (D y -A x ) n II;
c) (A x -D y ) m -A x -D y -A x III; and
d) (D y -A x ) m -D y -A x -D y IV,

wherein each of m, x, and y are independently an integer greater than or equal to 1, n is an integer greater than or equal to 2, A is an arabinonucleotide and D is a 2′-deoxyribonucleotide, wherein at least one instance of each of x and y is greater than or equal to 2.

8. The oligonucleotide of claim 1 , wherein said arabinonucleotides comprises a 2′ substituent selected from the group consisting of fluorine, hydroxyl, amino, cyano, azido, —HCH═CH 2 , —C═CH, alkyl, functionalized alkyl, alkoxy, and functionalized alkoxy groups.

9. The oligonucleotide of claim 8 , wherein said 2′ substituent is a lower C 1 -C 9 alkyl group.

10. The oligonucleotide of claim 9 , wherein said lower C 1 -C 9 alkyl group is selected from the group consisting of methyl, ethyl, and propyl groups.

11. The oligonucleotide of claim 8 , wherein said 2′ substituent is a functionalized alkyl group selected from the group consisting of methylamino, ethylamino, and propylamino groups.

12. The oligonucleotide of claim 8 , wherein said 2′ substituent is an alkoxy group selected from the group consisting of methoxy, ethoxy and propoxy groups.

13. The oligonucleotide of claim 8 , wherein said 2′ substituent is a functionalized alkoxy group with the formula —(CH 2 ) q —R, wherein q=2, 3, or 4 and —R is selected from the group consisting of —NH 2 , —OCH 3 , and —OCH 2 CH 3 groups.

14. The oligonucleotide of claim 8 , wherein said arabinonucleotides are 2′-fluoroarabinonucleotides (2′F-ANAs).

15. The oligonucleotide of claim 1 , wherein said oligonucleotide consists of 30 or fewer nucleotides.

16. The oligonucleotide of claim 15 , wherein said oligonucleotide consists of about 8 to about 25 nucleotides.

17. The oligonucleotide of claim 16 , wherein said oligonucleotide consists of about 18 nucleotides.

18. The oligonucleotide of claim 1 , wherein said oligonucleotide consists of about 5 to about 50 nucleotides.

19. The oligonucleotide of claim 18 , wherein said oligonucleotide consists of about 8 to about 40 nucleotides.

20. The oligonucleotide of claim 19 , wherein said oligonucleotide consists of about 12 to about 25 nucleotides.

21. The oligonucleotide of claim 1 , wherein each of said first segments comprises a plurality of arabinonucleotides.

22. The oligonucleotide of claim 1 , wherein each of said second segments comprises a plurality of 2′-deoxyribonucleotides.

23. The oligonucleotide of claim 1 , wherein at least one second segment comprises at least two 2′-deoxyribonucleotides.

24. The oligonucleotide of claim 1 , wherein said oligonucleotide commences and terminates with a first segment.

25. The oligonucleotide of claim 7 , wherein said oligonucleotide has structure III: (A x -D y ) m -A x -D y -A x .

26. The oligonucleotide of claim 23 , wherein said arabinonucleotides are 2′-fluoroarabinonucleotides (2′F-ANAs).

27. The oligonucleotide of claim 25 , wherein said arabinonucleotides are 2′-fluoroarabinonucleotides (2′F-ANAs).

28. The oligonucleotide of claim 14 , wherein all internucleotide linkages of the oligonucleotide consist of phosphorothioate linkages.

29. The oligonucleotide of claim 26 , wherein all internucleotide linkages of the oligonucleotide consist of phosphorothioate linkages.

30. The oligonucleotide of claim 27 , wherein all internucleotide linkages of the oligonucleotide consist of phosphorothioate linkages.

Assignees

• Damha Masad J
• Parniak Michael A
• Univ Mcgill

Inventors

• Damha Masad J
• Parniak Michael A

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/18

  for HIV · CPC title