Growth Factor Analogs

Abstract

The invention provides synthetic heparin-binding growth factor analogs of formulas I or II as given in the specification, having two peptide chains branched from a dipeptide branch moiety composed of at least one and preferably two trifunctional amino acid residues, which peptide chain or chains bind a heparin-binding growth factor receptor. 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 4  and R 6  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   + , or NH group or a corresponding acylated derivative, or is amino acid, a dipeptide or a tripeptide with an N-terminus NH 2 , NH 3   + , or NH group or a corresponding acylated derivative; 
 R 5  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 7 ;
 R 7  is an aliphatic C 1  to C 17  chain; 
 each X is a peptide chain that (i) has a minimum of three amino acid residues, (ii) has a maximum of about fifty amino acid residues, and (iii) binds a heparin-binding growth factor receptor (HBGFR); 
 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 ; 
 J 3  is a chain comprising a chain from 0 to about 50 atoms covalently bonded to J 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 7  wherein X and J 3  are synthetic peptide chains. 
     
     
         3 . The heparin-binding growth factor analog of  claim 8  which is a synthetic heparin-binding growth factor analog. 
     
     
         4 . The heparin-binding growth factor analog of  claim 7  wherein J 3  comprises a chain of a minimum of about 9 and a maximum of about 50 atoms, and J 3  is not found in the natural ligand of the heparin-binding growth factor receptor (HBGFR) which X binds. 
     
     
         5 . The heparin-binding growth factor analog of  claim 7  wherein binding of the heparin-binding growth factor analog to the heparin-binding growth factor receptor initiates a signal by the heparin-binding growth factor receptor. 
     
     
         6 . The heparin-binding growth factor analog of  claim 7  wherein binding of the heparin-binding growth factor analog to the heparin-binding growth factor receptor blocks signaling by the heparin-binding growth factor receptor. 
     
     
         7 . The heparin-binding growth factor analog of  claim 7  wherein J 1  and J 2  are diamine amino acid residues. 
     
     
         8 . The heparin-binding growth factor analog of  claim 13  wherein the diamine amino acid residue is a 2,3 diamino propionyl amino acid residue, a 2,4 diamino butylic amino acid residue, lysine or ornithine. 
     
     
         9 . The heparin-binding growth factor analog of  claim 7  wherein the covalent bond between X and J 1  and J 2  comprises an amide, disulfide, thioether, Schiff base, reduced Schiff base, imide, secondary amine, carbonyl, urea, hydrazone or oxime bond. 
     
     
         10 . The heparin-binding growth factor analog of  claim 7  wherein the side chains of J 1  and J 2  comprise reactive carboxyl groups. 
     
     
         11 . The heparin-binding growth factor analog of  claim 7  wherein X comprises an amino acid sequence found in any of FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, FGF-15, FGF-16, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21, FGF-22, FGF-23, HBBM (heparin-binding brain mitogen), HB-GAF (heparin-binding growth associated factor), HB-EGF (heparin-binding EGF-like factor) HB-GAM (heparin-binding growth associated molecule, also known as pleiotrophin, PTN, HARP), TGF-α (transforming growth factor-α), TGF-βs (transforming growth factor-βs), VEGF (vascular endothelial growth factor), EGF (epidermal growth factor), IGF-1 (insulin-like growth factor-1), IGF-2 (insulin-like growth factor-2), PDGF (platelet derived growth factor), RANTES, SDF-1, secreted frizzled-related protein-1 (SFRP-1), small inducible cytokine A3 (SCYA3), inducible cytokine subfamily A member 20 (SCYA20), inducible cytokine subfamily B member 14 (SCYB14), inducible cytokine subfamily D member 1 (SCYD1), stromal cell-derived factor-1 (SDF-1), thrombospondins 1, 2, 3 and 4 (THBS1-4), platelet factor 4 (PF4), lens epithelium-derived growth factor (LEDGF), midikine (MK), macrophage inflammatory protein (MIP-1), moesin (MSN), hepatocyte growth factor (HGF, also called SF), placental growth factor, IL-1 (interleukin-1), IL-2 (interleukin-2), IL-3 (interleukin-3), IL-6 (interleukin-6), IL-7 (interleukin-7), IL-10 (interleukin-10), IL-12 (interleukin-12), IFN-α (interferon-α), IFN-γ (interferon-γ), TNF-α (tumor necrosis factor-α), SDGF (Schwannoma-derived growth factor), nerve growth factor, neurite growth-promoting factor 2 (NEGF2), neurotrophin, BMP-2 (bone morphogenic protein 2), OP-1 (osteogenic protein 1, also called BMP-7), keratinocyte growth factor (KGF), interferon-γ inducible protein-20, RANTES, and HIV-tat-transactivating factor, amphiregulin (AREG), angio-associated migratory cell protein (AAMP), angiostatin, betacellulin (BTC), connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYCR61), endostatin, fractalkine/neuroactin, glial derived neurotrophic factor (GDNF), GRO2, hepatoma-derived growth factor (HDGF), and granulocyte-macrophage colony stimulating factor (GMCSF). 
     
     
         12 . The heparin-binding growth factor analog of  claim 7  wherein the peptide chains X are cross-linked or cyclized. 
     
     
         13 . The heparin-binding growth factor analog of  claim 7  wherein J 3  comprises between one and about thirty-three ethylene glycol units. 
     
     
         14 . The heparin-binding growth factor analog of  claim 7  wherein J 3  comprises a branched or unbranched, saturated or unsaturated alkyl chain of between one and about twenty carbon atoms. 
     
     
         15 . The heparin-binding growth factor analog of  claim 7  wherein J 3  comprises [NH 2 —(CH 2 ) p CO] q  wherein p is from 1 to about 10 and q is from 1 to about 20. 
     
     
         16 . The heparin-binding growth factor analog of  claim 7  wherein J 3  comprises a peptide sequence comprising from one to about 16 Gly residues.