Sequence-specific binding polymers for duplex nucleic acids

• US 5,166,315 A
• Filed: 06/20/1991
• Issued: 11/24/1992
• Est. Priority Date: 12/20/1989
• Status: Expired due to Term

• Current Assignee: AntiVirals, Inc. (Sarepta Therapeutics, Inc.)
• Original Assignee: Anti-Gene Development Group
• Inventors: Weller, Dwight D., Summerton, James E.
• Primary Examiner(s): Foelak, Morton
• Assistant Examiner(s): TRUONG, DUC
• Application Number:
  US07/719,732
• Time in Patent Office: 523 Days
• Field of Search: 525/384, 525/383, 525/385, 525/54.2, 525/54.3, 528/245, 528/417, 528/403, 528/406, 528/420, 528/423, 528/425
• US Class Current: 528/406
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• 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: B01J 2219/0072 Organic compounds
• 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
• CPC Class Codes: C12Q 1/6839 Triple helix formation or other higher order conformations in hybridisation assays

Abstract

A polymer composition effective to bind in a sequence-specific manner to a target sequence of a duplex polynucleotide containing different Watson-Crick basepair oreientaions. The composition includes an uncharged backbone with 5- or 6-membered cyclic backbone structures and selected bases attached to the backbone structures effective to hydrogen bond specifically with different oriented basepairs in the target sequence.

Claims

1. A polymer composition effective to bind in a sequence-specific manner to a target sequence of a duplex polynucleotide containing different Watson-Crick basepair orientations at selected target sequence positions, comprising a selected sequence of subunits having the form:

##STR8## where Y is a 2- or 3-atom length, uncharged subunit linkage group;

R is H, OH, or O-alkyl;

the 5'"'"'-methylene has a β

stereochemical orientation in the 5-membered ring and a uniform steroeochemical orientation in the 6-membered ring;

R_i has a β

sterochemical orientation; and

at least about 70% of R_i groups in the polymer have the following target basepair-orientation specificities;

(a) for a T;

A or U;

A orientation, R_i is diaminopurine;

(b) for a C;

G orientation, R_i is guanine or 6-thioguanine;

(c) for a G;

C orientation, R_i is selected from the group consisting of planar bases having the following ring structures and hydrogen bonding arrays, where B indicates the polymer backbone;

##STR9## where the * ring position may carry a hydrogen-bond acceptor group; and

(d) for an A;

T orientation, R_i is selected from the group consisting of planar bases having the following ring structures and hydrogen bonding arrays, where B indicates the polymer backbone;

##STR10## where the * ring position may carry a hydrogen-bond donating group.

2. The polymer composition of claim 1, wherein the subunit has the form:

##STR11##

3. The polymer composition of claim 1, wherein the subunit has the form:

##STR12##

4. The polymer composition of claim 3, wherein the it has the form:

##STR13##

5. The polymer composition of claim 1, for use in sequence-specific binding to a B-form DNA-DNA duplex nucleic acid, wherein the Y linkage groups is three atoms in length.

6. The polymer composition of claim 5, wherein the subunit in the polymer is selected from the group consisting of:

##STR14##

7. The polymer composition of claim 1, for use in sequence-specific binding to a A-form DNA-DNA duplex nucleic acid, wherein Y linkage groups is two atoms in length.

8. The polymer composition of claim 7, wherein the subunit in the polymer is selected from the group consisting of:

##STR15##

9. The polymer composition of claim 7, wherein the subunit in the polymer is selected from the group consisting of:

##STR16##

10. The polymer composition of claim 1, wherein the R_i structure:

##STR17##

11. The polymer of claim 1, wherein the R_i structure specific for a G:

C target orientation is selected from the group consisting of the following bases;

##STR18##

12. The polymer of claim 1, wherein the R_i structure specific for a A:

T target orientation is selected from the group consisting of the following bases;

##STR19##

13. The polymer composition of claim 12, wherein up to about 30% of the R_i groups in the polymer are cytosine, at polymer subunits corresponding to a G:

C or T;

A basepair orientation in the target sequence, and thymine, at polymer subunits corresponding to A;

T or C;

G basepair orientations in the target sequence.

14. The composition of claim 13, wherein the polymer contains one or more attached moieties effective to enhance the solubility of the polymer in aqueous medium.

15. The composition of claim 1, wherein the polymer contains one or more attached moieties effective to enhance the solubility of the polymer in aqueous medium.