2'-O-modified oligonucleotides

• US 5,872,232 A
• Filed: 06/06/1995
• Issued: 02/16/1999
• Est. Priority Date: 01/11/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Cook, Phillip Dan, Kawasaki, Andrew Mamoru
• Primary Examiner(s): LEGUYADER, JOHN L
• Application Number:
  US08/471,973
• Time in Patent Office: 1,351 Days
• Field of Search: 536/23.1, 536/24.3, 536/24.31, 536/24.32, 536/24.5, 536/25.1, 435/6, 435/91.1, 435/375
• US Class Current: 536/23.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/51 the non-active ingredient being a modifying agent
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• 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 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 15/1132 against retroviridae, e.g. HIV
• CPC Class Codes: C12N 15/1133 against herpetoviridae, e.g. HSV
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/315 : Phosphorothioates
• CPC Class Codes: C12N 2310/318 : where the PO2 is completely replaced, e.g. MMI or formacetal
• CPC Class Codes: C12N 2310/32 : of the sugar
• CPC Class Codes: C12N 2310/321 : 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 : 2'-R Modification
• CPC Class Codes: C12N 2310/33 : of the base
• CPC Class Codes: C12N 2310/333 : Modified A
• CPC Class Codes: C12N 2310/336 : Modified G
• CPC Class Codes: C12N 2310/3511 : intercalating or cleaving agent
• CPC Class Codes: C12N 2310/3521 : Methyl
• CPC Class Codes: C12N 2310/3523 : Allyl
• CPC Class Codes: C12N 2310/3527 : Other alkyl chain
• CPC Class Codes: C12N 2310/3531 : Hydrogen
• CPC Class Codes: C12N 2310/3533 : Halogen
• CPC Class Codes: C12N 2740/16322 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 9/0069 : acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• CPC Class Codes: C12Q 1/6813 : Hybridisation assays
• CPC Class Codes: C12Y 113/11012 : Linoleate 13S-lipoxygenase (1.13.11.12)

Abstract

Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'"'"'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.

Claims

1. A nuclease resistant compound that hybridizes with RNA or DNA, said compound comprising a plurality of covalently-bound nucleosides that individually include a ribose or deoxyribose sugar portion and a base portion, wherein:

said nucleosides are joined together by internucleoside linkages such that the base portion of said nucleosides form a mixed base sequence that is complementary to a RNA base sequence or to a DNA base sequence;

at least one of said nucleosides includes;

a base selected from adenine, thymine, uracil, and guanine; and

a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent, wherein the alkoxy moiety of said substituent is C₁ -C₂₀.

2. The compound of claim 1 wherein said 2'"'"'-aminoalkoxy is 2'"'"'-O-(aminoprop-3-yl) or 2'"'"'-O-(aminobut-4-yl).

3. The compound of claim 1 comprising 5 to 50 linked nucleosides.

4. The compound of claim 1 wherein at least two of said nucleosides are covalently bound through phosphorothioate, methyl phosphonate, or phosphate alkylate internucleoside linkages.

5. The compound of claim 1 wherein said 2'"'"'-imidazolylalkoxy is 2'"'"'-O- (imidazol-1-yl) prop-3-yl! or 2'"'"'-O- (imidazol-1-yl) but-4-yl!.

6. The compound of claim 1 wherein at least one of said nucleosides includes an adenine base and a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent.

7. The compound of claim 1 wherein at least one of said nucleosides includes a thymine base and a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent.

8. The compound of claim 1 wherein at least one of said nucleosides includes a guanine base and a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent.

9. The compound of claim 1 wherein at least two of said nucleosides each includes a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent.

10. The compound of claim 1 wherein at least three of said nucleosides each includes a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent.

11. The compound of claim 1 wherein said 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent is C₂ -C₂₀.

12. The compound of claim 1 wherein said 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent is C₃ -C₂₀.

13. The compound of claim 1 wherein said 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent is C₄ -C₂₀.

14. The compound of claim 1 wherein said 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent is C₅ -C₂₀.

15. The compound of claim 1 wherein at least one of said nucleosides includes a uracil base and a modified ribofuranosyl moiety bearing a 2'"'"'-aminoalkoxy or 2'"'"'-imidazolylalkoxy substituent.