Hydrogel-forming peptides

• US 10,526,371 B2
• Filed: 07/13/2016
• Issued: 01/07/2020
• Est. Priority Date: 07/13/2015
• Status: Active Grant

• Current Assignee: Universiteit Gent Vzw, Vrije Universiteit Brussel
• Original Assignee: Universiteit Gent Vzw
• Inventors: Hoogenboom, Richard, Madder, Annemieke, Ballet, Steven
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US15/743,357
• Publication Number:
  US 20180201648A1
• Time in Patent Office: 1,273 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

Provided are hydrogel-forming peptides that comprise at least one dyad of hydrophobic amino acid residues in which one is a β³- or β²-homo amino acid residue. The hydrogels derived from these peptides can be loaded with biological materials and can be used in physiological conditions.

Claims

1. A hydrogel-forming peptide comprising from 5 to 12 amino acid residues,

wherein the amino acid residues are selected from hydrophobic and hydrophilic amino acid residues;

wherein the hydrophobic amino acid residues are independently selected from alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan and cyclohexylalanine;

wherein the hydrophilic amino acid residues are independently selected from asparagine, glutamine, arginine, histidine, lysine, ornithine, aspartic acid and glutamic acid;

wherein the peptide further comprises one, two, or three dyads of hydrophobic amino acid residues, wherein at least one dyad contains a β

-homo amino acid residue;

wherein each dyad is separated from any other dyad or hydrophobic amino acid residue by a hydrophilic amino acid residue;

wherein the amino acid residues that are not a β

-homo amino acid residue are α

-amino acid residues;

wherein the N-terminus of the hydrogel-forming peptide;

bears two R^a groups each independently selected from R¹, or

bears one R¹ group and one group selected from C(═

Z)R¹, C(═

Z)ZR¹, C(═

Z)NHR¹ and C(═

Z)N(R¹)₂;

wherein each Z independently is O or S; and

each R¹ is independently selected from H, optionally substituted linear or branched C_1-10alkyl, optionally substituted C_3-10cycloalkyl, optionally substituted arylC_1-6alkyl and optionally substituted aryl;

wherein the C-terminus of the hydrogen forming peptide forms a group C(═

O)OR² or C(═

O)N(R²)₂; and

wherein each R² independently is selected from H, optionally substituted linear or branched C_1-10alkyl, optionally substituted C_3-10cycloalkyl, optionally substituted arylC_1-6alkyl, and optionally substituted aryl;

or a salt form thereof.

2. The hydrogel-forming peptide of claim 1, wherein the peptide has the following general formula I:

(R^a)₂—

(Y)_0,1-(Q-Y)_2-6-(Q)_0,1-R^b 

 

(I)

wherein each Q independently is a hydrophobic amino acid residue or a dyad of hydrophobic amino acid residues;

wherein one, two or three of said Q is a dyad of a hydrophobic α

-amino acid residue and a β

-homo amino acid residue;

each Y independently is a hydrophilic α

-amino acid residue;

the group (Y)_0,1 represents a bond or a hydrophilic α

-amino acid residue Y;

the group (Q)_0,1 represents a bond or a group Q;

(R^a)₂ represents two R^a groups, substituted on the terminal nitrogen of said peptide, the IV groups are each independently selected from R¹, or R^a groups represent one R¹ group and one group selected from C(═

Z)R¹, C(═

Z)ZR¹, C(═

Z)NH(R¹) and C(═

Z)N(R¹)₂;

wherein each Z independently is O or S; and

each R¹ is independently selected from H, optionally substituted linear or branched C_1-10alkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted arylC_1-6alkyl, and optionally substituted aryl;

R^b is a group OR² or N(R²)₂;

wherein each R² independently is selected from H, optionally substituted linear or branched C_1-10alkyl, optionally substituted C_3-10cycloalkyl, optionally substituted arylC_1-6alkyl, and optionally substituted aryl;

wherein the peptide has from 5 to 12 amino acid residues;

or a salt form thereof.

3. The hydrogel-forming peptide of claim 2, wherein —

(Y)_0,1—

is a bond;

the first Q-Y group represents a group —

X—

Y—

, wherein X is Phe, Tyr, or Trp;

Y is Glu, Gln, Asp or Asn;

two, three, or four -(Q-Y)—

groups are present, wherein one, two or three Q groups are dyads;

wherein each dyad independently is of formula -β

³homo-Phe-Phe-, or -β

³homo-Phe-Tyr-;

each Y independently is Lys, Glu, Gln, Asp or Asn; and

-(Q)_0,1- is a bond.

4. The hydrogel-forming peptide of claim 1,

wherein within dyads comprising a β

³-homo amino acid residue, the β

³-homo amino acid residue is positioned closest to the N-terminus; and

wherein within dyads comprising a β

²-homo amino acid residue, the β

²-homo amino acid residue is positioned closest to the C-terminus.

5. The hydrogel-forming peptide of claim 1, wherein at least one hydrophilic amino acid residue has a side chain that is positively charged at physiological pH and at least one hydrophilic amino acid residue has a side chain that is negatively charged at physiological pH.

6. The hydrogel-forming peptide of claim 1, wherein

each hydrophobic amino acid residue independently is selected from phenylalanine, tyrosine, tryptophan and cyclohexylalanine;

and

each hydrophilic amino acid residue independently is selected from asparagine, glutamine, arginine, lysine, aspartic acid and glutamic acid.

7. The hydrogel-forming peptide of claim 1, wherein each β

-homo amino acid residue is a β

3-homo amino acid residue.

8. The hydrogel-forming peptide of claim 7, wherein each β

3-homo amino acid is β

3-homo phenylalanine or β

3-homo tyrosine.

9. The hydrogel-forming peptide of claim 1, wherein the peptide is of formula

10. A hydrogel comprising the hydrogel-forming peptide of claim 1.

11. A composition comprising the hydrogel of claim 10 and one or more biological materials or one or more biologically active ingredients, or a combination thereof.

12. The composition of claim 11, wherein the biological material is a cell and/or the biologically active ingredient is an active pharmaceutical ingredient.

13. A process for preparing the hydrogel of claim 10 the process comprising:

dissolving the hydrogel-forming peptide in an aqueous medium containing a buffer, and allowing the formation of the hydrogel to take place.

14. The hydrogel-forming peptide of claim 1, wherein the hydrogel-forming peptide is a self-assembling hydrogel-forming peptide.

15. The hydrogel-forming peptide of claim 1, wherein the peptide is of formula: