Polyamine conjugated oligonucleotides

• US 5,138,045 A
• Filed: 07/27/1990
• Issued: 08/11/1992
• Est. Priority Date: 07/27/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Guinosso, Charles J., Cook, Philip D.
• Primary Examiner(s): Rollins, John W.
• Application Number:
  US07/558,663
• Time in Patent Office: 746 Days
• Field of Search: 536/27
• US Class Current: 536/24.5
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• 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 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

Oligonucleotide analogs are provided having improved cellular uptake and improved nuclease resistance. Modification of oligonucleotides through the attachment of nitrogenous moieties, especially polyamines, hydrazines and the like to nucleosidic portions of the analogs is disclosed. Oligonucleotides targeted at the tat region of HIV comprise certain preferred embodiments.

Claims

1. An oligonucleotide analog having at least one nucleoside modified by direct attachment of a polyamine at the 5'"'"' site of its sugar moiety.

2. The oligonucleotide analog of claim 1 wherein the oligonucleotide analog ranges in length from about 5 to about 50 nucleotide base unit.

3. The oligonucleotide analog of claim 1 wherein said nucleoside is thymidine.

4. The oligonucleotide analog of claim 1 wherein said polyamine is a primary amine, a hydrazine, a semicarbazide, or a thiosemicarbazide.

5. The oligonucleotide analog of claim 1 specifically hybridizable with the tat region of an HIV genome.

6. The oligonucleotide analog of claim 5 wherein said selected sequence has a thymidine at its 5'"'"' terminal end.

7. The oligonucleotide analog of claim 1 specifically hybridizable with a selected portion of a herpes genome.

8. The oligonucleotide of claim 1 specifically hybridizable with a selected portion of a papilloma genome.

9. the oligonucleotide analog of claim 1 wherein said polyamine has the structure:

space="preserve" listing-type="equation">H.sub.2 N(CH.sub.2).sub.n NH(CH.sub.2).sub.n NH(CH.sub.2).sub.n NH--

wherein n is an integer between 2 and 6.

10. The oligonucleotide analog of claim 9 wherein n is 4.

11. The oligonucleotide analog of claim 1 comprising at least one phosphorothioate group.