Synthetic heparin-binding factor analogs
View Patent ↗The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain, and preferably two peptide chains branched from a dipeptide branch moiety composed of two trifunctional amino acid residues, which peptide chain or chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a linker, which may be a hydrophobic linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.
1. A heparin-binding growth factor (HBGF) analog of formula II:
wherein:
R 3 and R 5 are each independently NH 2 , an acyl group with a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain including an N-terminus NH 2 , NH 3 + , NH group or a corresponding acylated derivative, or is an amino acid, a dipeptide or a tripeptide with an N-terminus NH 2 , NH 3 + , NH group or a corresponding acylated derivative;
R 4 is —OH, NH 2 , NH—R 6 , or is an amino acid, a dipeptide or a tripeptide with a C-terminus —OH, NH 2 , or NH—R 6 ;
R 6 is an aliphatic C 1 to C 17 chain;
each X comprises a peptide chain that is selected from SEQ ID NO: 6, SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19;
J 1 and J 2 are each independently a trifunctional alpha amino acid residue, wherein each X is covalently bonded through a side chain of J 1 or J 2 ;
Y is a linker comprising three amino hexanoic acid residues;
Z is a non-signaling peptide that comprises a heparin binding domain, comprising SEQ ID NO: 2;
n is 0 or 1, wherein when n=1 the synthetic peptide chains X are identical.
2. The heparin-binding growth factor analog of claim 1 wherein X and Z are synthetic peptide chains.
3. The heparin-binding growth factor analog of claim 1 wherein the heparin-binding growth factor analog has an avidity for heparin such that the heparin-binding growth factor analog binds heparin in 0.15 M NaCl, but is eluted by 1 M NaCl.
4. The heparin-binding growth factor analog of claim 1 wherein J 1 is, and if n=1, J 1 and J 2 is a diamine amino acid residue.
5. The heparin-binding growth factor analog of claim 4 wherein the diamine amino acid residue is a 2,3 diamino propionyl amino acid residue.
6. The heparin-binding growth factor analog of claim 4 wherein the diamine amino acid residue is lysine.
7. The heparin-binding growth factor analog of claim 4 wherein the diamine amino acid residue is ornithine.
8. The heparin-binding growth factor analog of claim 1 wherein the covalent bond between X and J 1 or, if n=1, J 1 and J 2 , comprises a peptide, disulfide, thioether, Schiff base, reduced Schiff base, imide, secondary amine, carbonyl, urea, hydrazone or oxime bond.
9. The heparin-binding growth factor analog of claim 1 wherein the side chain of J 1 and, if n=1, J 1 and J 2 , comprises a reactive carboxyl group.
10. The heparin-binding growth factor analog of claim 1 wherein the heparin-binding growth factor analog binds an FGF receptor.
11. The heparin-binding growth factor analog of claim 1 wherein the peptide chains X are cross-linked or cyclized.
12. The heparin-binding growth factor analog of claim 11 wherein the peptide chains X are cross-linked or cyclized by at least one disulfide, peptide, or thioether bond.