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 , and 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 selected from the group consisting of SEQ ID NO: 2-6.
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) is 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 J2 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 ,wherein formula II has the following formula (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, and q is from 1 to about 20.
8. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.