Dual chain synthetic heparin-binding growth factor analogs
View Patent ↗The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide 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 second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.
1. A compound 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 + , 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 4 is —OH, NH 2 , NH—R 7 , 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 comprises a sequence selected from SEQ ID NO:57, SEQ ID NO:58, and SEQ ID NO:64;
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 ;
R 6 is a linker comprising a chain from 1 to about 20 backbone carbons covalently bonded to J 1 and J 2 ;
Y is a linker comprising a chain from 0 to about 50 backbone carbons covalently bonded to J 2 and Z; and
Z is SEQ ID NO:2.
2. The compound of claim 1 wherein R 6 further comprises a linker that is not found in the natural ligand of the heparin-binding growth factor receptor (HBGFR) which X binds.
3. The compound of claim 1 wherein Y further comprises a linker that (i) hydrophobic, (ii) comprises a chain of a minimum of about 9 and a maximum of about 50 carbons, and (iii) is not found in the natural ligand of the heparin-binding growth factor receptor (HBGFR) which X binds.
4. The compound of claim 1 wherein J 1 and J 2 are diamine amino acid residues selected from the group consisting of 2,3 diamino propionyl amino acid, 2,4, diamino butylic amino acid, lysine and ornithine.
5. The compound of claim 1 wherein the covalent bond between X and J 2 comprises an amide, disulfide, thioether, Schiff base, reduced Schiff base, imide, secondary amine, carbonyl, urea, hydrazone or oxime bond.
6. The compound of claim 1 wherein the side chains of J 1 and J 2 comprise a reactive carboxyl group.
7. The compound of claim 1 of formula III:
wherein each m is independently from 1 to about 10, n is from 1 to about 6, each p is independently from 1 to about 10, q is from 1 to about 20, and X and Z are as defined in claim 1 .
8. The compound of claim 7 wherein Y comprises [NH 2 —(CH 2 ) p CO] q wherein p is from 1 to about 10 and q is from 1 to about 20.
9. A pharmaceutical composition comprising The compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.