High density peptide polymers

Patent metadata

Field	Value
Publication number	US-10980744-B2
Application number	US-201515502166-A
Country	US
Kind code	B2
Filing date	Aug 10, 2015
Priority date	Aug 8, 2014
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

Abstract

Described herein, inter alia, are peptide containing polymers, and methods of making and using the same.

First claim

What is claimed is:

1. A polymer having the formula:
R 1 -[M(O)] n —R 2

wherein,
n is an integer from 2 to 1000;
M is a polymerized ROMP polymerizable monomer;
O is independently a therapeutic polypeptide covalently attached to M through a covalent linker; wherein the therapeutic polypeptide is capable of treating a disease; and
R 1 and R 2 are independently terminal polymer moieties,

wherein 100% of the polymerized ROMP polymerizable monomers are each individually attached to a therapeutic polypeptide through a covalent linker,
wherein the polymerizable monomer is N-substituted-5-norbornene-2,3-dicarboximide, wherein the substitution comprises the therapeutic polypeptide, and
wherein the therapeutic polypeptide comprises from 5 to 2000 amino acids.

2. The polymer of claim 1 , wherein the polypeptide comprises from 2 to 6 arginine residues.

3. The polymer of claim 1 , wherein the polypeptide comprises 2 arginine residues.

4. The polymer of claim 2 , wherein the arginine residues are the carboxyl terminal residues of the therapeutic polypeptide.

5. The polymer of claim 1 , wherein the polypeptide does not comprise a carboxy terminal lysine residue.

6. The polymer of claim 1 , wherein the polypeptide is resistant to proteolysis relative to the unpolymerized polypeptide.

7. The polymer of claim 1 , wherein R 1 comprises a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

8. The polymer of claim 1 , wherein R 2 comprises a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

9. The polymer of claim 1 , wherein the polymer comprises a detectable moiety.

10. A method of administering a polypeptide to the interior of a cell comprising contacting said cell with the polymer of claim 1 .

11. The method of claim 10 , wherein said cell is in a subject.

12. The method of claim 11 , wherein said polymer is administered systemically to said subject.

13. A method of treating a disease in a subject, comprising administering to said subject a polymer of claim 1 .

14. A pharmaceutical composition including a pharmaceutically acceptable excipient and a polymer of claim 1 .

15. The polymer of claim 1 , wherein O is a cell growth or proliferation inhibitory peptide, an anti-inflammatory peptide, an anti-tumor or anti-cancer peptide, an anti-apoptotic peptide, anti-diabetic peptide, anti-obesity peptide, anti-infective peptide, anti-bacterial peptide, anti-viral peptide, a peptide for promoting cell growth and differentiation, a peptide for preventing pain, a peptide for preventing or treating neural degeneration or peptides for promoting neurogenesis.

16. The polymer of claim 1 , wherein O is Nesiritide, Ceruletide, Bentiromide, Exenatide, Gonadorelin, Enfuvirtide, Vancomycin, Icatibant, Secretin, Leuprolide, Glucagon recombinant, Oxytocin, Bivalirudin, Sermorelin, Gramicidin D, Insulin recombinant, Capreomycin, Salmon Calcitonin, Vasopressin, Cosyntropin, Bacitracin, Octreotide, Abarelix, Vapreotide, Thymalfasin, Insulin recombinant, Mecasermin, Cetrorelix, Teriparatide, Corticotropin, or Pramlintide.

17. The polymer of claim 1 , wherein O is tirofiban, captopril, eptifibatide, ziconotide, teriparatide, liraglutide, lanreotide, pramlintide, enfuvirtide, icatibant, ecallantide, tesamorelin, degarelix, mifamurtide, nesiritide, buserelin, gonadorelin, goserelin, histrelin, leuprolide, nafarelin, triptorelin, abarelix, cetrorelix, or ganirelix.

18. The polymer of claim 1 , wherein the therapeutic polypeptide is an active therapeutic moiety when included in the polymer.

19. The polymer of claim 1 , wherein the therapeutic polypeptide is an active therapeutic agent when released from the polymer.

20. A method of treating a disease in a subject, comprising administering to said subject the pharmaceutical composition of claim 14 .

21. A polymer having the formula:
R 1 -[M(O)] n —R 2

wherein,
n is an integer from 2 to 1000;
M is a polymerized ROMP polymerizable monomer;
O is independently a therapeutic polypeptide covalently attached to M through a covalent linker; wherein the therapeutic polypeptide is capable of treating a disease; and
R 1 and R 2 are independently terminal polymer moieties,

wherein 100% of the polymerized ROMP polymerizable monomers are each individually attached to a therapeutic polypeptide through a covalent linker,
wherein the therapeutic polypeptide comprises from 5 to 2000 amino acids, and
wherein M(O) is

wherein,
L 1 is independently a bond, —O—, —NH—, —COO—, —S—, —SO 2 —, —SO 3 —, —SO 4 —, —SO 2 NH—, —NHC(O)—, —C(O)NH—, —NHC(O)O—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and
R 4 is the therapeutic polypeptide.

22. The polymer of claim 21 , wherein the polypeptide comprises from 2 to 6 arginine residues.

23. The polymer of claim 22 , wherein the arginine residues are the carboxyl terminal residues of the therapeutic polypeptide.

24. The polymer of claim 21 , wherein the polypeptide comprises 2 arginine residues.

25. The polymer of claim 21 , wherein the polypeptide does not comprise a carboxy terminal lysine residue.

26. The polymer of claim 21 , wherein the polypeptide is resistant to proteolysis relative to the unpolymerized polypeptide.

27. The polymer of claim 21 , wherein R 1 comprises a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

28. The polymer of claim 21 , wherein R 2 comprises a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

29. The polymer of claim 21 , wherein the polymer comprises a detectable moiety.

30. The polymer of claim 21 , wherein O is a cell growth or proliferation inhibitory peptide, an anti-inflammatory peptide, an anti-tumor or anti-cancer peptide, an anti-apoptotic peptide, anti-diabetic peptide, anti-obesity peptide, anti-infective peptide, anti-bacterial peptide, anti-viral peptide, a peptide for promoting cell growth and differentiation, a peptide for preventing pain, a peptide for preventing or treating neural degeneration or peptides for promoting neurogenesis.

31. The polymer of claim 21 , wherein O is Nesiritide, Ceruletide, Bentiromide, Exenatide, Gonadorelin, Enfuvirtide, Vancomycin, Icatibant, Secretin, Leuprolide, Glucagon recombinant, Oxytocin, Bivalirudin, Sermorelin, Gramicidin D, Insulin re

Assignees

• Univ California

Inventors

• Blum Angela P
• Kammeyer Jacquelin K
• Gianneschi Nathan C

Classifications

• C07K14/001 Primary

  by chemical synthesis · CPC title

• C08G2261/164

  comprising organic end groups · CPC title

• C08G2261/94

  Applications in sensors, e.g. biosensors · CPC title

• C08G2261/3324

  derived from norbornene · CPC title

• C08G2261/90

  Applications · CPC title