Stable helical ionic polypeptides

Patent metadata

Field	Value
Publication number	US-10030103-B2
Application number	US-201615006118-A
Country	US
Kind code	B2
Filing date	Jan 26, 2016
Priority date	Nov 30, 2010
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The invention provides polymers comprising Formula I:

wherein monomer is a repeating unit comprising 2, 3, 4, 5, 6 or 7 carbon atoms and the monomers are linked together through amide or ester bonds; n is about 6 to about 1000; and Linker is an optionally substituted carbon chain that is optionally interrupted by moieties such as oxygen, nitrogen, sulfur, phosphorus, or silicon. Charge is a moiety having a positive or negative charge on a heteroatom, such as nitrogen, oxygen, phosphorus, or sulfur; where the Linker separates the monomer and the Charge by at least six linear atoms. The invention also provides methods of preparing the polymers and the copolymers and methods of using the polymers and copolymers, for example, as drug delivery systems, as membrane penetrating peptides, and as therapeutic agents.

First claim

The invention claimed is:

1. A polymer comprising Formula IA:

wherein
n is about 6 to about 1000;
q is 0 to about 5;
r is 0 to about 5;
R 13 is H, absent, an aromatic group, or an aliphatic group, wherein the aromatic group or aliphatic group is optionally substituted;
Linker is a chain of atoms comprising an ester, wherein the chain is 6 atoms or longer; and
* comprises a nitrogen heterocycle, a guanidinium group, a hydrazone, a hydrazide, a sulfonate, or a carboxylate;
or a salt thereof; wherein the term “about” refers to one or two integers greater than or less than the recited integer.

2. The polymer of claim 1 wherein the polymer is positively or negatively charged and is in the form of an α-helix.

3. The polymer of claim 2 wherein the α-helix form is stable at pH 1 to about pH 11 in an aqueous solution, and in an aqueous solution containing up to a 4 M concentration of NaCl.

4. The polymer of claim 1 wherein the polymer forms an α-helix in aqueous solution wherein the helix is stable at temperatures up to about 90° C.

5. The polymer of claim 1 wherein the backbone of the polymer of Formula IA comprises glutamic acid residues or aspartic acid residues.

6. The polymer of claim 1 wherein the Linker is a (C 6 -C 20 )alkyl group comprising an ester, wherein the (C 6 -C 20 )alkyl group is optionally interrupted by one, two, three, or four nitrogen atoms, oxygen atoms, phenyl groups, a sulfur atom, a triazole group, or a combination thereof, and wherein the (C 6 -C 20 )alkyl group is optionally substituted by one, two, three, four, or five oxo groups, hydroxy groups, (C 1 -C 4 )alkyl groups, pyridine groups, piperidine groups, pyrrolidine groups, monosaccharide groups, or a combination thereof.

7. The polymer of claim 2 wherein * comprises a nitrogen heterocycle, a guanidinium group, a sulfonate, or a carboxylate.

8. The polymer of claim 6 wherein the polymer comprises a polymer of Formula IIb or IIc:

wherein
n is about 10 to about 500;
m is 1 to about 10;
p is 1 to about 16;
q is 0 to about 5;
L is —R 1 , —NH—R 2 , or -Ph-CH 2 —NH—R 2 ;
R 1 comprises a triazole, a guanidinium, a carboxylate, a sulfonate, or a combination thereof; and
R 2 is —C(═O)-pyridine, sugar, phenyl, phenyl meta para substituted with a crown ether moiety; or (C 2 -C 10 )alkyl optionally substituted with one or more hydroxy, pyridine, piperidine, or pyrrolidine groups;
or a salt thereof.

9. The polymer of claim 8 wherein the polymer comprises a polymer of Formula IIa:

wherein
R 1 comprises a triazole a guanidinium, or a carboxylate.

10. The polymer of claim 8 wherein q is 1 to 5.

11. The polymer of claim 8 wherein q is 1 to about 5.

12. The polymer of claim 8 wherein the polymer comprises a polymer of Formula IIIa or IIIb:

wherein
R 1 comprises a triazole or a guanidinium.

13. The polymer of claim 12 wherein q is 1 to about 5.

14. The polymer of claim 9 wherein the polymer comprises Formula IIIc:

wherein
R 1 comprises a triazole or a guanidinium; and
m is 1 to 9.

15. The polymer of claim 1 wherein n is 100 or greater.

16. The polymer of claim 1 wherein the polymer comprising Formula IA is a block copolymer or a random copolymer.

17. A method for delivering molecular cargo to a cell comprising:
contacting a cell with a composition comprising a polymer of claim 1 and molecular cargo, and optionally contacting the cell with an effective transfection-promoting amount of nocodazole; wherein the polymer adopts a secondary structure, where the secondary structure comprises an α-helix or a β-sheet; under conditions sufficient to transfect the cell with the molecular cargo; wherein the molecular cargo comprises, DNA, RNA, a protein, a small molecule drug, or a diagnostic agent.

18. A method for inhibiting bacterial growth comprising:
contacting bacteria with a composition comprising a polymer of claim 1 , wherein the polymer adopts a secondary structure, where the secondary structure comprises an α-helix or a β-sheet; under conditions sufficient to inhibit the growth of the bacteria.

19. A method for inhibiting cancer cell growth comprising:
contacting cancer cells with a composition comprising a polymer of claim 1 , wherein the polymer is in the form of a secondary structure, where the secondary structure comprises an α-helix or a β-sheet; under conditions sufficient to inhibit the growth of the cancer cells.

20. A method for destabilizing a cell membrane or causing pore formation in a cell comprising:
contacting the cell with a composition comprising a polymer claim 1 , wherein the polymer is in the form of a stable α-helix; under conditions sufficient contact the cell with the polymer, whereby the polymer causes pore formation in the cell.

21. The polymer of claim 8 wherein the polymer comprises a polymer of Formula P7 or P8:

22. The polymer of claim 21 wherein n is 55, m is 2, and p is 8.

Assignees

• Univ Illinois

Inventors

• Cheng Jianjun
• Lu Hua

Classifications

• C08L77/04

  Polyamides derived from alpha-amino carboxylic acids (C08L77/10 takes precedence) · CPC title

• A01N43/36

  five-membered rings · CPC title

• C08G69/22

  Beta-lactams · CPC title

• A61K31/785

  Polymers containing nitrogen · CPC title

• C08L77/02

  Polyamides derived from omega-amino carboxylic acids or from lactams thereof (C08L77/10 takes precedence) · CPC title