Amphipathic oligonucleotides and polynucleotides having potent antiviral activity

• US 6,130,324 A
• Filed: 08/10/1999
• Issued: 10/10/2000
• Est. Priority Date: 08/11/1998
• Status: Expired due to Fees

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Broom, Arthur D., Thorpe, Robyn
• Primary Examiner(s): Elliot, George C.
• Assistant Examiner(s): LACOURCIERE, KAREN A
• Application Number:
  US09/371,909
• Time in Patent Office: 427 Days
• Field of Search: 536/23.1, 536/24.1, 536/24.5, 536/24.31, 536/24.33, 536/24.3, 536/25.3, 536/25.35, 435/91.5, 435/6
• US Class Current: 536/23.1
• 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

The present invention provides novel compositions that show potent antiviral activity against both DNA and RNA viruses. In particular, the present invention provides oligo- and polyribonucleotides with potent antiviral activity against HIV and HCMV. These compositions are thought to operate in a novel fashion at an early stage of viral infection, meeting the need for alternatives or synergistic therapies to the toxic treatments currently available. The present invention also discloses methods for synthesizing oligo- and polyribonucleotides showing antiviral activity.

Claims

1. A composition comprising a number, n, of nucleoside monomers that are represented by the formula:

##STR5## wherein R¹ is a member selected from the group consisting of alkyl, aralkyl, cycloalkyl, and unsaturated alkyl;

R² and R³ are independently selected from the group consisting of H, SCH₃, NH₂, alkylthio, and alkylamino;

R⁴ is a member selected from the group consisting of hydroxy, fluoro, alkoxy, mercaptoalkyl, alkoxyalkoxy, hydroxyalkoxy, and aminoalkoxy;

n is from about 12 to 1000; and

wherein the nucleoside monomers are joined by phosphodiester or phosphorothioate linkages.

2. The composition of claim 1, wherein R¹ is an unsaturated alkyl.

3. The composition of claim 2, wherein n is greater than 31.

4. The composition of claim 1, wherein the monomers are joined by phosphodiester linkages.

5. The composition of claim 1, wherein n is greater than 31.

6. The composition of claim 1, wherein n from about 100 to 1000.

7. A composition comprising a number, n, of nucleoside monomers that are represented by the formula:

##STR6## wherein R¹ is a member selected from the group consisting of aralkyl or cycloalkyl;

R² and R³ are independently selected from the group consisting of H, SCH₃, NH₂, alkylthio, and alkylamino;

R⁴ is a member selected from the group consisting of hydroxy, fluoro, alkoxy, mercaptoalkyl, alkoxyalkoxy, hydroxyalkoxy, and aminoalkoxy;

n is from about 12 to 1 000; and

wherein the nucleoside monomers are joined by phosphodiester or phosphorothioate linkages.

8. The composition of claim 7, wherein n is greater than 31.

9. The composition of claim 7, wherein n is from about 100 to 1000.

10. The composition of claim 7, wherein the monomers are joined by phosphodiester linkages.

11. A composition comprising a number, n, of nucleoside monomers that are represented by the formula:

##STR7## wherein R¹ is a member selected from the group consisting of alkyl, aralkyl, cycloalkyl, and unsaturated alkyl;

R² is selected from the group consisting of SCH₃, alkylthio, and alkylamino;

R³ is selected from the group consisting of H, SCH₃, NH₂, alkylthio, and alkylamino;

R⁴ is a member selected from the group consisting of hydroxy, fluoro, alkoxy, mercaptoalkyl, alkoxyalkoxy, hydroxyalkoxy, and aminoalkoxy;

n is from about 12 to 1000; and

wherein the nucleoside monomers are joined by phosphodiester or phosphorothioate linkages.

12. The composition of claim 11, wherein n is greater than 31.

13. The composition of claim 11, wherein n is from about 100 to 1000.

14. The composition of claim 11, wherein the monomers are joined by phosphodiester linkages.

15. A composition comprising a number, n, of nucleoside monomers that are represented by the formula:

##STR8## wherein R¹ is a member selected from the group consisting of alkyl, aralkyl, cycloalkyl, and unsaturated alkyl;

R² is selected from the group consisting of H, SCH₃, NH₂, alkylthio, and alkylamino;

R³ is selected from the group consisting of SCH₃, NH₂, alkylthio, and alkylamino;

R⁴ is a member selected from the group consisting of hydroxy, fluoro, alkoxy, mercaptoalkyl, alkoxyalkoxy, hydroxyalkoxy, and aminoalkoxy;

n is from about 12 to 1000; and

wherein the nucleoside monomers are joined by phosphodiester or phosphorothioate linkages.

16. A composition comprising a number, n, of nucleoside monomers that are represented by the formula:

##STR9## wherein R¹ is a member selected from the group consisting of alkyl, aralkyl, cycloalkyl, and unsaturated alkyl;

R² and R³ are independently selected from the group consisting of H, SCH₃, NH₂, alkylthio, and alkylamino;

R⁴ is a member selected from the group consisting of fluoro, mercaptoalkyl, alkoxyalkyl, hydroxyalkoxy, and aminoalkoxy;

n is from about 12 to 1000; and

wherein the nucleoside monomers are joined by phosphodiester or phosphorothioate linkages.

17. Oligonucleotides and polynucleotides comprising a number, n, of nucleoside monomers that are represented by the formula:

##STR10## wherein n is from about 12 to 1000 and the nucleoside monomers are joined by phosphodiester linkages.

18. The oligonucleotides and polynucleotides of claim 17, wherein n is from about 100 to 1000.

19. A method of making poly(1-propargylinosinic acid) comprising the steps of:

(a) reacting propargyl bromide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and inosine to produce 1-propargylinosine;

(b) converting 1-propargylinosine to 1-propargylinosine-5'"'"'-monophosphate;

(c) converting 1-propargylinosine-5'"'"'-monophosphate to 1-propargylinosine-5'"'"'-diphosphate; and

(d) polymerizing 1-propargylinosine-5'"'"'-diphosphate with polynucleotide phosphorylase to produce poly(1-propargylinosinic acid).

20. A composition prepared according to the method of claim 19.