Supramolecular hydrogel of fMLF-based molecules and use thereof

Patent metadata

Field	Value
Publication number	US-10232037-B2
Application number	US-201415115385-A
Country	US
Kind code	B2
Filing date	May 29, 2014
Priority date	Feb 3, 2014
Publication date	Mar 19, 2019
Grant date	Mar 19, 2019

Abstract

The invention relates to the application of peptides that can self-assemble to form supramolecular nanofibrils and hydrogels, hydrogel compositions containing the self-assembled supramolecular nanofibrils, and methods of uses and making the hydrogel compositions.

First claim

What is claimed:

1. A peptide comprising up to 35 amino acids, said amino acids having a formylated or acetylated N-terminal residue and a C-terminal residue selected from the group of 2-Nal or 2-Nal D , wherein the peptide, when introduced into aqueous medium, self-assembles to form a hydrogel.

2. The peptide according to claim 1 , wherein the amino acids are all D-amino acids.

3. The peptide according to claim 1 , wherein the amino acids are a mixture of L-amino acids and D-amino acids.

4. The peptide according to claim 1 , wherein the formylated N-terminal residue is f-Met or f-Ala.

5. The peptide according to claim 1 , wherein said C-terminal residue is 2-Nal D .

6. The peptide according to claim 5 , wherein said peptide exhibits enhanced resistance to proteinase digestion compared to an identical peptide lacking the C-terminal 2-Nal D residue.

7. The peptide according to claim 6 , wherein said proteinase is proteinase K.

8. The peptide according to claim 1 , wherein said peptide is up to 10 amino acids.

9. A peptide having a formylated (f) or acetylated (Ac) N-terminal residue and being selected from the group consisting of f-MLF-(2-Nal) (SEQ ID NO: 1), f-MLF-(2-Nal D ), f-ML-(2-Nal)-(2-Nal), f-MIVIL-(2-Nal) (SEQ ID NO: 2), f-MIVIL-(2-Nal D ), f-MIFL-(2-Nal) (SEQ ID NO: 3), f-MIFL-(2-Nal D ), f-MFINRWLFS-(2-Nal) (SEQ ID NO: 4), f-MFINRWLFS-(2-Nal D ), f-MFFINILTL-(2-Nal) (SEQ ID NO: 5), f-MFFINILTL-(2-Nal D ), f-AWKYMV D -(2-Nal), f-AWKYMV D -(2-Nal D ), f-M D L D F D -(2-Nal D ), f-M D L D -(2-Nal D )-(2-Nal D ), f-M D I D V D I D L D -(2-Nal D ), f-M D I D F D L D -(2-Nal), f-M D F D I D N D R D W D L D F D S D - (2-Nal D ), f-M D F D F D I D N D I D L D T D L D -(2-Nal D ), f-A D W D K D Y D M D V D -(2-Nal D ), Ac-ML-(2-Nal)-(2-Nal D ), and Ac-M D L D -(2-Nal)-(2-Nal n ).

10. The peptide according to claim 5 , wherein said C-terminal 2-Nal D residue is further connected to a Tn antigen (N-acetylgalactosamine) through a serine residue or at a side chain through a ε-amine of a lysine residue.

11. An immunogenic conjugate comprising an antigenic peptide conjugated to the peptide according to claim 1 .

12. The immunogenic conjugate according to claim 11 , wherein the antigenic peptide comprises an epitope that induces an antibody mediated immune response.

13. The immunogenic conjugate according to claim 11 , wherein the antigenic peptide comprises an epitope that induces a T-cell mediated immune response.

14. A hydrogel composition comprising an aqueous medium and a peptide according to claim 1 , wherein the peptide self assembles to form nanofibrils.

15. The hydrogel composition according to claim 14 further comprising an agent selected from the group consisting of an antibiotic agent, a chemotherapeutic agent, an immunotherapeutic agent, and an antigenic agent that comprises an epitope that induces either an antibody mediated or T-cell mediated immune response.

16. A method for eliciting an inflammatory response in a subject comprising:
administering to a subject in need thereof a therapeutically effective amount of the hydrogel composition according to claim 14 , wherein said administering is effective to release the peptide from the hydrogel over a period of time and the inflammatory response extends for a duration dependent on the peptide release from the hydrogel.

17. A method for inducing neutrophil accumulation in vivo comprising:
administering to a subject in need thereof a therapeutically effective amount of the hydrogel composition according to claim 14 , wherein said administering is effective to release the formyl peptide over a period of time exceeding 12 hours, thereby inducing neutrophil accumulation at the site of administration for a duration dependent on the peptide release from the hydrogel.

18. A method for treating a cancerous condition comprising:
administering to a subject having a cancerous condition a therapeutically effective amount of the hydrogel composition according to claim 14 , wherein said administering is effective to inhibit tumor growth or shrink tumor size.

19. A method of treating a bacterial infection comprising:
administering to a patient having a bacterial infection a therapeutically effective amount of the hydrogel composition according to claim 14 , wherein said administering is effective to treat the bacterial infection.

20. A method of making a hydrogel composition comprising introducing a peptide according to claim 1 into an aqueous medium, wherein the peptide self-assembles to form nanofibrils.

Assignees

• Univ Brandeis
• Childrens Medical Center

Inventors

• Zhao Fan
• Li Jingyu
• Luo Hongbo R
• Xu Bing

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A01N25/04

  Dispersions, {emulsions, suspoemulsions, suspension concentrates} or gels (foams A01N25/16) · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title