Antiviral oligonucleotides targeting HBV

• US 8,067,385 B2
• Filed: 07/10/2008
• Issued: 11/29/2011
• Est. Priority Date: 09/13/2002
• Status: Expired due to Fees

• Current Assignee: Replicor Inc.
• Original Assignee: Replicor Inc.
• Inventors: Juteau, Jean-Marc, Vaillant, Andrew
• Primary Examiner(s): McGarry; Sean
• Application Number:
  US12/170,847
• Publication Number:
  US 20090042827A1
• Time in Patent Office: 1,237 Days
• Field of Search: 435/6, 435/91.1, 435/455, 536/23.1, 514/44
• US Class Current: 514/44.R
• 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. An antiviral oligonucleotide formulation comprising at least one phosphorothioated antiviral oligonucleotide, 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, hepatitis B virus, a member of the flaviviridae or hepatitis C virus.

2. The oligonucleotide formulation of claim 1, wherein said formulation comprises 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, cytosine and thymine.

3. The oligonucleotide formulation of claim 1, wherein said formulation contains an oligonucleotide that is a heteropolymer comprised of alternating adenosine and cytosine residues.

4. The oligonucleotide formulation of claim 1, wherein said formulation contains an oligonucleotide consisting of SEQ ID NO:

24.

5. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one 5-methylcytosine base.

6. The oligonucleotide formulation of claim 1, wherein said formulation contains an oligonucleotide that is a heteropolymer comprised of alternating adenosine and guanosine residues.

7. The oligonucleotide formulation of claim 1, wherein said formulation contains an oligonucleotide consisting of SEQ ID NO:

26.

8. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one phosphodiester linkage.

9. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one 2′

-O methyl modification to the ribose moiety.

10. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one 2′

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

11. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one 2′

- modification to the ribose moiety.

12. The oligonucleotide formulation of claim 1, wherein said oligonucleotide has all ribose moieties modified with a 2′

-O methyl modification.

13. The oligonucleotide formulation of claim 1, wherein said oligonucleotide has all ribose moieties modified with a 2′

-O (2-methoxyethyl) modification.

14. The oligonucleotide formulation claim 1, wherein said oligonucleotide has all ribose moieties modified with a 2′

ribose modification.

15. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one methylphosphonate linkage.

16. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one phosphorodithioated linkage.

17. The oligonucleotide formulation of claim 1, wherein said oligonucleotide further comprises at least one locked nucleic acid.

18. The oligonucleotide formulation of claim 1, wherein said oligonucleotide is a concatemer consisting of two or more oligonucleotide sequences joined by a linker.

19. The oligonucleotide formulation of claim 1, wherein said oligonucleotide is linked or conjugated at one or more nucleotide residues, to a molecule modifying the characteristics of the oligonucleotide to obtain one or more characteristics selected from the group consisting of higher stability, lower serum interaction, higher cellular uptake, higher viral protein interaction, an improved ability to be formulated for delivery, a detectable signal, higher antiviral activity, better pharmacokinetic properties, specific tissue distribution and lower toxicity.

20. An antiviral pharmaceutical composition comprising a therapeutically effective amount of at least one pharmacologically acceptable, antiviral oligonucleotide formulation according to claim 1, and a pharmaceutically acceptable carrier.

21. The antiviral pharmaceutical composition of claim 20, 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, intratrachael injection and intravenous injection.

22. The antiviral pharmaceutical composition of claim 20, wherein said composition further comprises at least one other antiviral drug in combination.