Novel amphiphilic nucleic acid conjugates

• US 4,904,582 A
• Filed: 06/11/1987
• Issued: 02/27/1990
• Est. Priority Date: 06/11/1987
• Status: Expired due to Fees

• Current Assignee: Synthetic Genomics, Inc.
• Original Assignee: Synthetic Genomics, Inc.
• Inventors: Tullis, Richard H.
• Primary Examiner(s): Wax, Robert A.
• Application Number:
  US07/061,874
• Time in Patent Office: 992 Days
• Field of Search: 435/6, 435/172.3, 435/240.2, 435/243, 436/501, 424/44, 536/27, 935/2, 935/4, 935/33, 935/34, 935/36, 935/77, 935/78
• US Class Current: 435/6.18
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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

Novel oligonucleotide conjugates are provided, where oligonucleotides are joined through a linking arm to a hydrophobic moiety. The resulting conjugates are more efficient in membrane transport, so as to be capable of crossing the membrane and effectively modulating a transcriptional system. In this way, the compositions can be used in vitro and in vivo, for studying cellular processes, protecting mammalian hosts from pathogens, and the like.

Claims

1. A method for inhibiting the maturation or translation of a messenger RNA in a cell, said method comprising:

contacting said cell with a composition comprising an oligonucleotide sequence complementary to a transcription product of said cell and a group covalently linked to said oligonucleotide sequence to provide an amphiphilic molecule, whereby said composition migrates into the cell interior resulting in the inhibition of maturation and/or translation of said transcription product.

2. A method according to claim 1, wherein said cell is in culture and said composition is introduced into the nutrient medium.

3. A method according to claim 1, wherein said oligonucleotide is of from about 6 to 30 nucleotides.

4. A method according to claim 3, wherein at least one of said oligonucleotides has a phosphate as the phosphorus moiety.

5. A method according to claim 3, wherein at least one of said oligonucleotides has a phosphonate with an alkyl group of from 1 to 3 carbon atoms as the phosphorus moiety.

6. A method according to claim 1, wherein said group is a hydrophobic aromatic group.

9. A method according to claim 1, wherein said group is a polyalkyleneoxy group, wherein said alkylenes are of from 2 to 10 carbon atoms.

10. A method according to claim 9, wherein said polyalkyleneoxy group is from about 6 to 200 units.

7. A method according to claim 7, wherein said aromatic group is a trityl group.

8. A method according to claim 7, wherein said aromatic group is a fluorescein group.

11. A cell comprising a composition comprising an oligonucleotide sequence complementary to a transcription product of said cell and an amphiphilic or hydrophobic group covalently linked to said oligonucleotide sequence to provide an amphiphilic molecule.

12. A cell according to claim 11, wherein said cell is in culture.

13. A composition of matter comprising:

an oligonucleotide sequence of at least six nucleotides complementary to a transcriptional product of a cell;

an amphiphilic group comprising a polyalkyleneoxy group, wherein said alkylenes are of from 2 to 10 carbon atoms;

a linker of at least one atom covalently bonded to said oligonucleotide sequence and to said amphiphilic group.

14. A composition of matter according to claim 13, wherein said oligonucleotide is of from about 6 to 30 nucleotides.

15. A composition of matter according to claim 13, wherein at least one of said oligonucleotides has a phosphate as the phosphorus moiety.

16. A composition of matter according to claim 13, wherein at least one of said oligonucleotides has a phosphonate with an alkyl group of from 1 to 3 carbon atoms as the phosphorus moiety.

17. A composition of matter according to claim 13, wherein said linking group includes at least one of an amino, quinone, thioether, or amide group.

18. A composition of matter according to claim 13, wherein said oligonucleotide sequence is complementary at least in part to a non-coding region.

19. A composition of matter according to claim 13, wherein said oligonucleotide sequence is complementary at least in part to a coding region.