Antiviral oligonucleotides targeting viral families

• US 8,008,270 B2
• Filed: 04/09/2008
• Issued: 08/30/2011
• Est. Priority Date: 09/13/2002
• Status: Active Grant

• Current Assignee: Replicor Inc.
• Original Assignee: Replicor Inc.
• Inventors: Juteau, Jean-Marc, Vaillant, Andrew
• Primary Examiner(s): ZARA, JANE J
• Application Number:
  US12/100,181
• Publication Number:
  US 20090156527A1
• Time in Patent Office: 1,238 Days
• Field of Search: 435/6, 435/91.1, 435/455, 435/91.31, 435/458, 514/44, 514/1, 514/2, 536/23.1, 536/24.5
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/11 DNA or RNA fragments; Modified forms thereof DNA or RNA not used in recombinant technology, C07H21/00; Non-coding nucleic acids having a biological activity
• CPC Class Codes: C12N 15/115 Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Random sequence oligonucleotides that have antiviral activity are described, along with their use as antiviral agents. In many cases, the oligonucleotides are greater than 40 nucleotides in length. Also described are methods for the prophylaxis or treatment of a viral infection in a human or animal, and a method for the prophylaxis treatment of cancer caused by oncoviruses in a human or animal. The methods typically involve administering to a human or animal in need of such treatment, a pharmacologically acceptable, therapeutically effective amount of at least oligonucleotide that does not act by a sequence complementary mode of action.

Claims

1. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the herpesviridae.

27. The method of any of claims 1 to 26, wherein said formulation contains an oligonucleotide which comprises at least one deoxyribonucleic acid and one ribonucleic acid.

28. The method of any of claims 1 to 26, wherein said formulation contains an oligonucleotide that is a heteropolymer comprised of dinucleotide repeats, wherein each dinucleotide contains two different nucleotides selected from the group consisting of adenosine, guanosine, cytidine, thymine or uridine.

29. The method of any of claims 1 to 26, wherein said formulation contains an oligonucleotide that is a heteropolymer comprised of alternating adenosine and cytidine residues.

30. The method of any of claims 1 to 26, wherein said formulation contains an oligonucleotide consisting of SEQ ID NO:

24.

31. The method of any of claims 1 to 26, wherein said oligonucleotide further comprises at least one 5-methylcytosine base.

32. The method of any of claims 1 to 26, wherein said formulation contains an oligonucleotide that is a heteropolymer comprised of alternating adenosine and guanosine residues.

33. The method of any of claims 1 to 26, wherein said formulation contains an oligonucleotide consisting of SEQ ID NO:

26.

34. The method of any of claims 1 to 26, wherein said oligonucleotide further comprises at least one 2′

-O methyl modification to the ribose moiety.

35. The method of any of claims 1 to 26, wherein said oligonucleotide further comprises at least one 2′

-O (2-methoxyethyl) modification to the ribose moiety.

36. The method of any of claims 1 to 26, wherein said oligonucleotide further comprises at least one 2′

-modification to the ribose moiety.

37. The method of any of claims 1 to 26, wherein said oligonucleotide has all ribose moieties modified with a 2′

-O methyl modification.

38. The method of any of claims 1 to 26, wherein said oligonucleotide has all ribose moieties modified with a 2′

-O (2-methoxyethyl) modification.

39. The method of any of claims 1 to 26, wherein said oligonucleotide has all ribose moieties modified with a 2′

ribose modification.

40. The method of any of claims 1 to 26, wherein said oligonucleotide is a concatemer consisting of two or more oligonucleotide sequences joined by a linker.

41. The method of any of claims 1 to 26, adapted for delivery by a mode selected from the group consisting of intraocular injection, oral ingestion, enterally, inhalation, cutaneous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intrathecal injection, intratracheal injection and intravenous injection.

42. The method of any of claims 1 to 26, wherein said oligonucleotide is administered with at least one other antiviral drug in combination.

43. The method of any of claims 1 to 26, wherein said oligonucleotide is between 30 and 120 nucleotides in length.

2. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets HSV-1.

3. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets HSV-2.

4. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets cytomegalovirus.

5. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the hepadnaviridae.

6. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets hepatitis B virus.

7. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the poxviridae.

8. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the paramyxoviridae.

9. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets respiratory syncytial virus.

10. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets parainfluenza virus.

11. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the bunyaviridae.

12. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets hantavirus.

13. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the filoviridae.

14. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets Ebola virus.

15. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets Marburg virus.

16. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the flaviviridae.

17. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets yellow fever virus, dengue virus or West Nile virus.

18. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets hepatitis C virus.

19. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the orthomyxoviridae.

20. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets influenza virus.

21. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets influenza A virus.

22. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets influenza B virus.

23. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the togaviridae.

24. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the coronaviridae.

25. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the rhabdoviridae.

26. A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one pharmacologically acceptable phosphorothioate oligonucleotide, wherein said oligonucleotide is fully phosphorothioated, wherein said oligonucleotide is between 20 and 120 nucleotides in length, wherein the antiviral activity of said oligonucleotide occurs by a non-sequence dependent mode of action, and wherein said oligonucleotide targets a member of the arenaviridae.